VIRGEN MILAGROSA UNIVERSITY

FOUNDATION
COLLEGE OF MEDICINE S.Y. 2014-2015
SANCARLOS CITY, PANGASISNAN

Prepared by:
Urban, Lanie J.
Salvador, Romarie Joy D.
Valdez, Ligaya O.
Nagila, Pradeep
Pestano, Mary Grace C.

(GROUP 8)

AIDS (Acquired Immune Deficiency

Syndrome)
HIV infection is a condition that can gradually destroy the immune system,
which makes it harder for the body to fight infections. When this happens, the
person
has
AIDS
(acquired
immune
deficiency
syndrome).Human
immunodeficiency virus (HIV) causes HIV infection and AIDS. The virus attacks
the immune system. As the immune system weakens, the body is vulnerable to
life-threatening infections and cancers. Once a person has the virus, it stays
inside the body for life.

Incidence Rate Worldwide

Global situation and trends: Since the beginning of the epidemic, almost
75 million people have been infected with the HIV virus and about 36 million
people have died of HIV. Globally, 35.3 million [32.238.8 million] people were
living with HIV at the end of 2012. An estimated 0.8% of adults aged 1549 years
worldwide are living with HIV, although the burden of the epidemic continues to
vary considerably between countries and regions. Sub-Saharan Africa remains
most severely affected, with nearly 1 in every 20 adults living with HIV and
accounting for 71% of the people living with HIV worldwide.

Incidence Rate in the Philippines

Officially, the Philippines is a low-HIV-prevalence country, with less than
0.1 percent of the adult population estimated to be HIV-positive.
MANILA, Philippines - The scenario presented to the Philippines regarding
the rise of HIV and AIDS in the country despite a global decline has worsened. As
of January 2013, the Department of Health (DOH) AIDS Registry in the Philippines
reported 10,514 people living with HIV/AIDS.

Risk factors
When HIV/AIDS first surfaced in the United States, it mainly affected men
who had sex with men. However, now it's clear that HIV is also spread through
heterosexual sex.
Anyone of any age, race, sex or sexual orientation can be infected, but you're
at greatest risk of HIV/AIDS if you:

Have unprotected sex. Unprotected sex means having sex without

using a new latex or polyurethane condom every time. The risk increases if
you have multiple sexual partners.

Have another STI. Many sexually transmitted infections (STIs) produce

open sores on your genitals. These sores act as doorways for HIV to enter
your body.

Use intravenous drugs. People who use intravenous drugs often share
needles and syringes. This exposes them to droplets of other people's blood.

Are an uncircumcised man. Studies indicate that lack of circumcision

increases the risk of heterosexual transmission of HIV.

STRUCTURE OF HIV

HIV is a member of the lentivirus family of retroviruses. On electron

microscopy, HIV appears as spherical particles that are approximately 110 nm in
diameter, with knoblike projections on the surface of the virus and a coneshaped viral core. 44 particles contain two copies of an RNA genome, each of
which is approximately 10,000 base pairs in length and encodes nine genes.
The genetic structure of HIV-1 is similar to that of all retro-viruses. The
genome is organized into three major regions (gag, pol, and env) that are flanked
by the HIV-1 promoter or long terminal repeat.
a. gag region- contains the structural genes for HIV
i.e., matrix, capsid, nucleocapsid, and two small peptides
b. pol region- contains the genes for the viral enzymes needed to carry
out the life cycle
i.e., reverse transcriptase, integrase, and protease
c. env region- encodes the genes for the viral envelope proteins
i.e., gp160, which is cleaved to gp120 and gp41
Six regulatory genes:

a. tat (transactivating gene)

- upregulates transcription of the genome
b. rev
- coordinates the expression of the regulatory and nonregulatory
genes by orchestrating
the transport of spliced and unspliced RNA transcripts out of the
nucleus
c. nef
helps the virus evade the host immune response by
downregulating expression of CD4
and major histocompatibility complex (MHC) class I molecules on
the cell surface and
also contributes to viral virulence
d. vpu
- reduces host cell CD4 expression and is involved in cellular release
of virions
e. vpr
is important for infection of nondividing cells by facilitating
nuclear localization of the
viral preintegration complex and also regulates cell cycle arrest
f. vif
is important for virion assembly, infectivity, inactivation of the
host cell antiviral factor
APOBEC3G,46 and gp120 membrane insertion.
The reverse transcriptase of HIV is very error-prone and introduces
mutations at a rate of approximately 1 in 104, or about one mutation in every
virus produced. In addition, during normal replication, the reverse transcriptase
enzyme jumps from one strand of nucleic acid to another to complete the
synthesis of daughter strands. This strand-jumping enables recombination
between different viral strains infecting the same cell. Mutation and
recombination permit the virus to respond rapidly to environmental changes
such as those related to receptor availability, host immune responses, and
antiretroviral drugs.
Two different HIV species have been identified: HIV-1 and HIV-2. Those
isolates of HIV-1 that have been globally identified can be classified into the
three major phylogenetic groups: M (main), N (neither M nor O), and O (outlier).
The M group has predominantly been responsible for the global HIV epidemic.
This group can be further subdivided into 10 distinct subtypes or clades, termed
subtypes A to J. Patients can be infected with more than one clade, and
recombination of viruses from different clades can occur.

LIFE CYCLE OF HIV

HIV can infect multiple cells in your body, including brain cells, but its
main target is the CD4 lymphocyte, also called aT-cell or CD4 cell. When a CD4
cell is infected with HIV, the virus goes through multiple steps to reproduce itself

and create many more virus particles. The process is broken up into the following
steps:

1.

Binding and Fusion: This is the process by which HIV binds to a specific
type of CD4 receptor and a co-receptor on the surface of the CD4 cell. This is
similar to a key entering a lock. Once unlocked, HIV can fuse with the host cell
(CD4 cell) and release its genetic material into the cell.

2.

Reverse
Transcription:
A
special enzyme called reverse
transcriptase changes the genetic material of the virus, so it can be
integrated into the host DNA.

3.

Integration: The virus new genetic material enters the nucleus of the
CD4 cell and uses an enzyme called integrase to integrate itself into your own
genetic material, where it may hide and stay inactive for several years.

4.

Transcription: When the host cell becomes activated, and the virus uses
your own enzymes to create more of its genetic materialalong with a more
specialized genetic material which allows it make longer proteins.

5.

Assembly: A special enzyme called protease cuts the longer

HIV proteins into individual proteins. When these come together with the
virus genetic material, a new virus has been assembled.

6.

Budding: This is the final stage of the virus life cycle. In this stage, the
virus pushes itself out of the host cell, taking with it part of the membrane of
the cell. This outer part covers the virus and contains all of the structures
necessary to bind to a new CD4 cell and receptors and begin the process
again.

PATHOLOGY OF AIDS

1. Seroconversion illness this occurs in 1 to 6 weeks after acquiring the

infection. The feeling is similar to a bout of flu.
2. Asymptomatic infection After seroconversion, virus levels are low and
replication continues slowly. CD4 and CD8 lymphocyte levels are normal.
This stage has no symptoms and may persist for years together.
3. Persistent generalised lymphadenopathy (PGL) The lymph nodes in
these patients are swollen for three months or longer and not due to any
other cause.
4. Symptomatic infection This stage manifests with symptoms. In
addition, there may be opportunistic infections. This collection of
symptoms and signs is referred to as the AIDS-related complex (ARC) and
is regarded as a prodrome or precursor to AIDS.
5. AIDS this stage is characterized by severe immunodeficiency. There are
signs of life-threatening infections and unusual tumours. This stage is
characterized by CD4 T-cell count below 200 cells/mm3.

Phases
1. Early, Acute Phase
Transient viremia
Widespread seeding of lymphoid tissue
Temporary fall in CD4+ T cells
Seroconversion and control of viral replication by generation of
CD8+ antiviral T cells
Self-limited acute illness
Recovery and near-normal CD4+ T cell counts occur within 8-12
weeks
2. Middle, Chronic Phase
Clinical latency with continued vigorous viral replication mainly in
the lymphoid tissue
Gradual decline of CD4+ counts

 Persistent generalized lymphoid enlargement, with no constitutional

symptoms
This phase may last for years
Toward the end of this phase, fever, rash, fatigue, and viremia
appear
May last from7-10 years
3. Final, Crisis Phase
Rapid decline in host defences
Low CD4+ counts (<200 cells/L), weight loss,
opportunistic infections and secondary neoplasms
Stage recognized as full- blown AIDS

diarrhea,

Clinical Features of Full-Blown AIDS

Varieties of opportunistic infections occur. Pneumocystis carinii pneumonia

occurs in 50% of patients; other pathogens are Candida, cytomegalovirus,
typical and atypical mycobacteria, Cryptococcus neoformans, Toxoplasma
gondii, Cryptosporidium, Herpes simplex virus, papovaviruses, and
Histoplasma capsulatum.
A wide spectrum of pyogenic bacteria infections occurs.
A variety of malignant neoplasms occur. Aggressive Kaposi sarcoma is the
most common; it is more common in homosexuals.
KS lesions are composed of spindle cells that form vascular channels.
These lesions are monoclonal neoplasms that are associated with Human
Herpes virus-8, also called KS herpes virus.
Aggressive B cell non-Hodgkin lymphomas, especially at extranodal sites,
frequently involving brain, occur at rates 120-fold higher than in general
population. Uncommon body cavity lymphoma that involves pleural,
peritoneal, and pericardial spaces is also found.
Clinical neurologic involvement

Diagnostic Tests for HIV and AIDS

Blood tests are the most common way to diagnose the human
immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency
syndrome (AIDS). These tests look for antibodies to the virus that are present in
the blood of infected individuals. People exposed to the virus should get tested
immediately.
Because it can take from six weeks to six months to develop antibodies to
the virus, follow-up tests may be needed. Your doctor will ask about your
symptoms, medical history and risk factors and perform a physical examination.
The primary tests for diagnosing HIV and AIDs include:
1. ELISA Test ELISA, which stands for enzyme-linked immunosorbent
assay, is used to detect HIV infection. If an ELISA test is positive, the
Western blot test is usually administered to confirm the diagnosis. If an
ELISA test is negative, but you think you may have HIV, you should be
tested again in one to three months.ELISA is quite sensitive in chronic HIV
infection, but because antibodies aren't produced immediately upon
infection, you may test negative during a window of a few weeks to a few
months after being infected. Even though your test result may be negative

2.
3.

4.

5.

during this window, you may have a high level of the virus and be at risk
of transmitting infection.
Home Tests The only home test approved by the U.S. Food and Drug
Administration is called the Home Access Express Test, which is sold in
pharmacies.
Saliva Tests A cotton pad is used to obtain saliva from the inside of
your cheek. The pad is placed in a vial and submitted to a laboratory for
testing. Results are available in three days. Positive results should be
confirmed with a blood test.
Viral Load Test This test measures the amount of HIV in your blood.
Generally, it's used to monitor treatment progress or detect early HIV
infection. Three technologies measure HIV viral load in the blood
reverse transcription polymerase chain reaction (RT-PCR), branched DNA
(bDNA) and nucleic acid sequence-based amplification assay (NASBA). The
basic principles of these tests are similar. HIV is detected using DNA
sequences that bind specifically to those in the virus. It is important to
note that results may vary between tests.
Western Blot This is a very sensitive blood test used to confirm a
positive ELISA test result.

Signs and Symptoms

Symptoms of AIDS are caused by the deterioration of the immune system and
the decline of CD4+ T cells, which are the immune system's key infection
fighters. As soon as HIV enters the body, it begins to destroy these cells. Some
common symptoms include:

Diarrhea that lasts for more than a week

Dry cough
Memory loss, depression and neurological disorders
Pneumonia
Profound, unexplained fatigue
Rapid weight loss
Recurring fever or profuse night sweats
Red, brown, pink or purplish blotches on or under the skin or inside the
mouth, nose or eyelids
Swollen lymph glands in the armpits, groin or neck
White spots or unusual blemishes on the tongue, in the mouth, or in the
throat

TREATMENT
There is no cure for AIDS at this time. But treatments are available to
manage symptoms. Treatment can also improve the quality and length of life for
those who have already developed symptoms.
Antiretroviral therapy suppresses the replication of the HIV virus in the
body. A combination of antiretroviral drugs, called antiretroviral therapy
(ART), also known as highly active antiretroviral therapy (HAART), is very
effective in reducing the amount of HIV in the bloodstream. This is
measured by the viral load (how much free virus is found in the blood).

Preventing the virus from reproducing (replicating) can improve T-cell

counts and help the immune system recover from HIV infection.
Vaccine and Treatment Updates
1. Vaccine
In May of 2004, the Walter Reed Army Institute of Research in
conjunction with the US National Institute of Allergy and Infectious disease
began a US-based Phase I trial of LFn-p24, a new vaccine developed by
Avant Immunotherapeutics. This novel vaccine combines an anthrax
bacterium protein with the HIV Gag protein.
In June of 2004, researchers from Malawi and the US are working
together to evaluate the vaccine candidate MRK-Ad5.
In 2003 the US Center for Disease Control (CDC) is involved in the trials
of two vaccine trials: VAX003 and VAX004 that are evaluating the gp 120based vaccines produced by the private company VaxGen. In 2005, the
CDC is working on developing new animal models to evaluate vaccines
considering future vaccine trials in Africa and Thailand.
In 2002, the US NIAD worked with The Vaccine Research Center (VRC)
on the Phase I clinical trials (VRC 004) of the multiclade, multigene DNA
vaccine. This DNA vaccine uses the "prime-boost" strategy brought by the
recombinant adenovirus type 5 (rAd5) acting as a vector to deliver HIV
immunogens. This approach stimulates the immune system by first using
a DNA priming vaccine and boosting later with the rAd5 vaccine. The initial
study findings showed the vaccine was safe and effective. In December of
2003, a larger scale Phase I study was launched and in July of 2004, the
first Phase I study of the booster vaccine was developed. In January of
2005, subjects of the original VRC 004 study received the booster
vaccination to test the efficacy of the entire sequence.
2. Antiretroviral Treatment (ARV )Treatment in Resource Limited
Settings
The WHO's goal has been that by the end of 2005, 3 million people
should have access to antiretroviral treatment. The WHO reccomends that
in resource limited settings, HIV infected individuals should start ARV even
if they are not showing clnical symptoms of AIDS. The first line regimin
should consist of 2 nucleoside analogs and either a non-nucleoside or
abacavir, or a protease inhibitor. Patients in these settings should have
well documented past medical histories, current medical conditions, and
other medication use.

Prevention

The main way to prevent HIV infection is to avoid activities that put you at
risk, such as having sex without a condom and sharing needles and other
injecting equipment.If you have HIV you can pass it on to others if you
have sex without a condom, or share needles, syringes, or other injecting
equipment.

The best way to prevent HIV and other sexually transmitted infections
(STIs) is to use a condom for penetrative sex and a dental dam for oral
sex.HIV can be passed on before ejaculation, through pre-come and
vaginal secretions, and from the anus.

Lubricant, or lube, is often used to enhance sexual pleasure and safety,

by adding moisture to either the vagina or anus during sex. It can make
sex safer by reducing the risk of vaginal or anal tears caused by dryness
or friction, and it can also prevent a condom from tearing.Only waterbased lubricant (such as K-Y Jelly) rather than an oil-based lubricant (such
as Vaseline or massage and baby oil) should be used with condoms.Oilbased lubricants weaken the latex in condoms and can cause them to
break or tear.

Dental damis a small sheet of latex that works as a barrier between the
mouth and the vagina or anus to reduce the risk of STIs during oral sex.It
is important that dams are only used once, the same side of the dam is
always kept against the body, and a new dam is used if a new area of the
body is being stimulated. A dam should never be moved from the vagina
to the anus or vice versa.

Sharing needles and injecting equipment. If you inject drugs, don't

share needles or syringes, or other injecting equipment such as spoons
and swabs, as this could expose you to HIV and other viruses found in the
blood, such as hepatitis C.

References:
Robbins Pathologic Basis of Disease 6th Edition
http://www.mayoclinic.org/diseases-conditions/hiv-aids/basics/risk-factors/con20013732
http://www.aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/hiv-in-yourbody/hiv-lifecycle/
http://www.health24.com/Medical/HIV-AIDS/Symptoms-and-diseasesassociated/Symptoms-and-phases-of-HIV-infection-Aids-20120721
http://www.ucsfhealth.org/conditions/aids/signs_and_symptoms.html
https://web.stanford.edu/group/virus/retro/2005gongishmail/HIV.html
http://www.aidsvaccine05.org/Home.aspx
http://www.iavireport.org/specials/OngoingTrialsofPreventiveHIVVaccines.pdf

INCIDENCE
MANILA,
Philippines
The
scenario presented to the Philippines
regarding the rise of HIV and AIDS in the

country despite a global decline has

worsened.
The Department of Health said on
Wednesday, May 1, that there had been
more than 1,000 cases of HIV or AIDS in
the Philippines within the first quarter of
2013
According to the Philippine HIV
and AIDS Registry, 370 new cases were
reported in March 2013. This brought the
total cases reported to 1,089 this year,
leading to 12,791 cases since 1984.
Whereas 2012 saw an average of 8 HIV
cases daily, 12 cases of HIV are now
being reported. Most of the cases (96%)
were males. The median age was 28
years (age range: 17-63 years). The 2029 age group (55%) had the most
number of cases, the DOH said.

The mode of transmission for 364

cases was sexual contact while 6 cases
were of drug users who shared
contaminated needles.
The DOH noted that 85% of the cases in
this new report came from male-to-male
sex (MSM), a rise from the 82% reported
in May.Overseas Filipino workers (OFWs)
accounted for 128 of the 370 new cases,
with 120 of the cases being those of
males. The report mentions 99% of the
infected OFWs acquired the AIDS virus
through sexual contact, with 1% caused
by injected drug use.
Despite some headway towards curing
HIV, it would be a good idea to practice
safe, responsible sex, and get tested for
HIV regularly if you are sexually active. Rappler.com
HIV lifecycle diagram, steps
identified:
1. Free virus circulates in the
bloodstream
2. Virus binds to cell at two receptor
sites
3. Virus penetrates cell, HIV empties its
contents into the cell
4. Single strands of viral RNA are
converted into double-stranded DNA by
the reverse transcriptase enzyme
5. Viral DNA is combined with the cell's
own DNA by the integrase enzyme
6. When the infected cell divides, the
viral DNA is read and long chains of
proteins are made. It activates the HIV
DNA, which makes the raw material for
new viruses
7. Sets of viral protein chains come
together
8. Immature virus pushes out of the cell
taking some cell membrane with it
9. Immature virus breaks free of the
infected cell
10. The protein chains in the new viral
particle are cut by protease enzyme into
individual proteins that combine to make
a working virus (the new HIV virus
matures)
HIV primarily targets
o CD4+Th cells
o Dendritic cells
o Macrophages
o CD8+Tc cells
o DoubleThymic + cells
o NK cells
o Neural cell of monocyte origin

HIV spreads to lymphoid surface of

mucosal surface
o Thymus and bone may be infected
o CNS cells
T cells and macrophages in
semen and renal epithelium
Major finding
Decreased CD4+ Th cells =
800-1000 cells/L of blood
Increased CD8+ T-cells = 6001200 cells/L
Reversal of the CD4/CD8 T-cell
ratioApoptosis
HIV infected cells express
surface antigens and are
targets for Tc-mediated lysis
HIV cells shed soluble viral
envelop protein gp120 which
induces apoptosis of Uninfected
- T lymphocytes
- Neurons
- Monocytes
Diagnosis may be
Serologically negative
Serologically positive
Early stage HIV
Antibodies appear from
Blood products appx. 4-7 weeks
Sexual transmission appx.6-14
months
Acquired
immune
deficiency
syndrome (AIDS) is caused by the HIV or
human immunodeficiency virus. The
infection causes progressive destruction
of the cell-mediated immune (CMI)
system, primarily by eliminating CD4+ Thelper lymphocytes.
Decreased immunity leads to
opportunistic infections and certain
cancers. Opportunistic infections are
caused by organisms that do not cause
infections in
Time taken for AIDS to develop
AIDS indicates advanced HIV
disease and has no cure and is
considered fatal. The time from HIV
infection to death however depends on
the
management
with
anti-HIV
medications instituted on time and
continued over long term.
The time period usually ranges from 6
months (rarely) to 15+ years. In the

United Kingdom the average time is

around 12 years.
Pathology of AIDS
HIV infection passes through a series of
steps or stages before it turns into AIDS.
These stages of infection as outlined in
1993 by the Centers for Disease Control
and prevention are:
1. The primary HIV infection
phase (or acute seroconversion illness)
The acute phase of HIV infection
(also
called
acute
sero-conversion
illness) begins as soon as seroconversion has taken place. Seroconversion means the point in time when
a persons HIV status converts or
changes from being HIV negative to HIV
positive. This also usually coincides with
the time when an HIV antibody test will
show that a person is HIV positive.
Sero-conversion usually occurs four
to eight weeks after an individual has
been infected with the HI virus. About
30%-60% of people infected with HIV
develop flu-like symptoms such as sore
throat, headache, mild fever, fatigue,
muscle and joint pains, swelling of the
lymph nodes, rash, and (occasionally)
oral ulcers. These symptoms usually last
from between one and two weeks.
Because of the rapid replication of
the virus, the HIV viral load is usually
very high during the acute phase.
Immediate and aggressive treatment
with anti-retroviral therapy (ART) at this
stage may be effective in reducing the
viral load to undetectable levels, or even
in eradicating the virus.
2. The
Asymptomatic
Latent
Phase
The second phase of HIV infection is
the asymptomatic latent or silent phase.
In this stage, an infected person displays
no symptoms. Infected individuals are
often not even aware that they are
carrying the HI virus in this stage, and
may therefore unwittingly infect new sex
partners.
Even though the infected person may
be ignorant of its presence, the virus
nevertheless remains active in the body
during this stage and it continues to
damage and undermine its victims
immune system. A positive HIV antibody

test is often the only indication of HIV

infection during this latent phase.
HIV-infected people can remain
healthy for a long time, show no
symptoms and carry on with their work
in a normal way. Some people remain
HIV positive for many years without any
manifestation of clinical disease while
others may deteriorate rapidly, develop
Aids and die within months. In some
cases the only symptom during this
phase is swollen glands.
3. Minor symptomatic phase of
HIV disease
In the third phase of infection, minor and
early symptoms of HIV disease usually
begin to manifest.
This phase usually starts when people
with HIV antibodies begin to present with
one or more of the following symptoms:

Mild to moderate swelling of the

lymph nodes in the neck, armpits
and groin

Occasional fevers

Shingles (or Herpes zoster)

Skin rashes and nail infections

Sores in the mouth that come and

go

Recurrent upper respiratory tract

infections

Weight loss up to 10% of the

persons usual body weight

General feelings of tiredness and

non-feeling-well
4. Major symptomatic phase of
HIV infection and opportunistic
diseases
Major symptoms and opportunistic
diseases begin to appear as the immune
system continues to deteriorate. At this
point, the CD4 cell count becomes very
low while the viral load becomes very
high.
There is a small group of patients who
develop AIDS very slowly, or never at all.
These
patients
are
called
nonprogressors.
The pathological spectrum of HIV
infection is changing as the infection
spreads into new communities with
different
potential
opportunistic
diseases, and as medical science devises
drugs against HIV replication.
People are diagnosed with AIDS when
they have certain signs or symptoms

defined by the U.S. Centers for Disease

Control and Prevention (CDC).
The CDC's definition of AIDS includes:
Less than 200 CD4+ T cells per
cubic
millimeter
of
blood,
compared with about 1,000 CD4+
T cells for healthy people. CD4+T
cells are white blood cells that
play an important role in the
body's immune system. These
cells are destroyed by HIV. Even
when a HIV-positive person feels
well and is not experiencing any
symptoms of the disease, CD4+ T
cells are being infected by HIV.
CD4+ T cells accounting for less
than
14
percent
of
all
lymphocytes, a type of white
blood cell.
One of more of the illnesses listed
below:
Candidiasis
of
bronchi,
esophagus, trachea or lungs
Cervical cancer that is invasive
Coccidioidomycosis
that
has
spread
Cryptococcosis that is affecting
the body outside the lungs
Cryptosporidiosis affecting the
intestines and lasting more than a
month
Cytomegalovirus disease outside
of the liver, spleen or lymph
nodes
Cytomegalovirus retinitis that
occurs with vision loss
Encephalopathy that is HIVrelated
Herpes simplex including ulcers
lasting more than a month or
bronchitis,
pneumonitis
or
esophagitis
Histoplasmosis that has spread
Isosporiasis
affecting
the
intestines and lasting more than a
month
Kaposi's sarcoma
Lymphoma that is Burkitt type,
immunoblastic or that is primary
and affects the brain or central
nervous system
Mycobacterium avium complex or
disease caused by M kansasii
Mycobacterium tuberculosis in or
outside the lungs
Other species of mycobacterium
that has spread

Pneumocystis jiroveci, formerly

called carinii, pneumonia
Pneumonia that is recurrent
Progressive multifocal
leukoencephalopathy
Salmonella septicemia that is
recurrent
Toxoplasmosis of the brain, also
called encephalitis
Wasting syndrome caused by HIV
infection
Symptoms also may include anxiety,
dementia, depression and insomnia.

LAB TYPES AND WHY THEY ARE

IMPORTANT
Once you have tested positive for
HIV, your HIV care provider will probably
ask you to take a number of laboratory
tests. The list may include:
CD4/T-cell count: A count of your CD4
cells gives a general measure of the
health of your immune system, and is a
good
measurement
of
immunosuppression. A normal CD4 cell
count is more than 500 cells per cubic
millimeter (mm3) of blood. If you have a
CD4 count of fewer than 200/mm3, you
will be diagnosed as having AIDS.
Why its important: This is a good
measure of your risk of opportunistic
infections and the strength of your
immune system. It will give you and your
healthcare provider the information you
need to decide the best way to treat
your HIV disease.
CD4 Percentage: This measures how
many of your white blood cells are
actually CD4 cells. This measurement is
more stable than CD4 counts over a long
period of time, but, for most people, the
CD4 count remains a more reliable
measure of immune function than CD4
percentage.
Why its important: This measurement is
less likelyto vary in between blood tests
than CD4 counts (which can vary from
month to month or day to day).
Viral Load (VL): This test measures the
amount of HIV in your blood.
Why its important: The goals of HIV
treatment are to keep your viral load at
undetectable levels and to keep your
CD4 count high. A viral load test offers a
good indicator of how well your
treatment is working to achieve those
goals.
Complete Blood Count (CBC): This is
a measure of the concentration of red

blood cells, white blood cells, and

platelets in a sample of your blood.
Why its important: A CBC is one of the
most commonly ordered blood tests. It
can
reveal
infections,
anemia
(abnormality in your red blood cells), and
other medical issues.
Serum Chemistry Panel: This test
helps provide information about your
body's metabolism. It gives your doctor
information about how your kidneys and
liver are working, and can be used to
evaluate your blood sugar levels,
calcium levels, etc.
Why
its
important:
Some
HIV
medications can have serious side
effects, and this test helps your
healthcare provider to monitor the
impact of your medications on your
bodys ability to function normally.
Sexually Transmitted Disease (STD)
Screening: These screening tests check
for syphilis, gonorrhea and chlamydia.
Why its important: Having an STD, can
make it easier to pass HIV to others.
Untreated STDs can also be damaging to
your own immune system.
PAP Smear (Cervical and Anal): This
is a screening test for abnormal cells
that could become cancerous. It involves
using a swab to take cell samples
directly from the cervix and anus.
Why its important: For women living
with HIV, abnormal cell growth in the
cervix is common, and abnormal anal
cells are common for both men and
women who are HIV-positive. These
abnormal cells may become cancerous if
they arent treated.
Hepatitis A, B, and C tests: These
blood tests check for current or past
infection with Hepatitis A, B, or C...
Why its important: Some people who
are living with HIV are also coinfected
with hepatitis. Checking you for hepatitis
A, B, and C can help your provider to
determine if you need to be treated, or if
you are a candidate for one of the
existing hepatitis vaccines.
Tuberculosis (TB) Skin Test: This skin
test checks for exposure to TB. A positive
skin test does not mean you have active
TB, but it means you will need further
evaluation and possible treatment.
Why its important: Untreated TB can be
a deadly disease for people living with
HIV. Early screening and treatment will
help limit your risk of severe illness, as

well
as
lower
your
chances
of
transmitting TB to others if you do have
it.
Toxoplasmosis Screening: This test
checks for exposure to a parasite that
can cause severe damage to the brain,
eyes, and other organs in people with
weakened immune systems.
Why its important: Toxoplasmosis can be
a deadly opportunistic infection for
people living with HIV. Your clinician
needs to know if you have been exposed
to
the
parasite
that
causes
toxoplasmosis or are at risk for exposure.
This will help your healthcare provider to
decide
if
you
need
preventative
treatment. If your CD4 count falls below
100/mm3, you will probably need to do
another screening, even if your earlier
screens were negative.
Fasting Lipid Panel (Cholesterol and
Triglycerides): These tests measure
your total cholesterol level, as well as
give you information about the different
types of fat proteins in your body.
Why
its
important:
Some
HIV
medications can affect your cholesterol
levels and the way your body processes
and stores fat. This can make you prone
to other medical problems, including
heart problems.
Fasting Glucose (blood sugar): This
test measures your blood sugar levels to
check for signs of pre-diabetes or
diabetes.
Why
its
important:
Some
HIV
medications can affect blood sugar
levels,
potentially
leading
to
complications like diabetes.
HIV infection is a condition that
can gradually destroy the immune
system, which makes it harder for the
body to fight infections. When this
happens, the person has AIDS (acquired
immune deficiency syndrome).
Causes
Human immunodeficiency virus (HIV)
causes HIV infection and AIDS. The virus
attacks the immune system. As the
immune system weakens, the body is
vulnerable to life-threatening infections
and cancers. Once a person has the
virus, it stays inside the body for life.
The virus is spread (transmitted) personto-person in any of the following ways:

Through sexual contact -- including oral,

vaginal, and anal sex
Through blood -- via blood transfusions
(now extremely rare in the U.S.) or
needle sharing
From mother to child -- a pregnant
woman can spread the virus to her fetus
through their shared blood circulation, or
a nursing mother can transmit it to her
baby through her breast milk
The virus is not spread by:
Casual contact such as hugging
Mosquitoes
Participating in sports
Touching items that were touched by a
person infected with the virus
HIV and blood or organ donation:
HIV is not spread to a person who
donates blood or organs. People who
donate organs are never in direct
contact with people who receive them.
Likewise, a person who donates blood is
never in contact with the person
receiving it. In all these procedures,
sterile needles and instruments are
used.
But HIV can be spread to a person
receiving blood or organs from an
infected donor. To reduce this risk, blood
banks and organ donor programs check
(screen) donors, blood, and tissues
thoroughly.
People at high risk of getting HIV include:
Injection drug users who share needles
Infants born to mothers with HIV who did
not receive HIV treatment during
pregnancy
People who have unprotected sex,
especially with people who have other
high-risk behaviors, are HIV-positive, or
have AIDS
People who received blood transfusions
or clotting products between 1977 and
1985, before screening for the virus
became standard practice
Sexual partners of those who engage in
high-risk activities (such as injection
drug use or anal sex)
After HIV infects the body, the virus has
been found in saliva, tears, nervous
system tissue and spinal fluid, blood,
semen (including pre-seminal fluid,
which is the liquid that comes out before
ejaculation), vaginal fluid, and breast
milk. Only blood, semen, vaginal

secretions, and breast milk have been

shown to transmit infection to others.
Symptoms
Symptoms related to acute HIV infection
(when a person is first infected) are often
flu-like:

Diarrhea
Fever
Headache
Mouth sores, including yeast
infection (thrush)
Muscle stiffness or aching
Night sweats
Rashes of different types
Sore throat
Swollen lymph glands
Many people have no symptoms
when they are diagnosed with
HIV.

Acute HIV infection progresses over a

few weeks to months to become an
asymptomatic
HIV
infection
(no
symptoms). This stage can last 10 years
or longer. During this period, the person
can still spread the virus to others.
Almost all people infected with HIV, if
they are not treated, will develop AIDS. A
small group of patients develop AIDS
very slowly or never at all. These
patients are called nonprogressors. Many
seem to have genes that prevent the
virus from significantly damaging their
immune system.
People with AIDS have had their immune
system damaged by HIV. They are very
susceptible to (easily get) infections that
do not normally develop in people with a
healthy
immune
system.
These
infections
are
called
opportunistic
infections.
Common symptoms are:
Chills
Fever
Rash
Sweats (particularly at night)
Swollen lymph glands
Weakness
Weight loss
Exams and Tests

The
HIV
ELISA
and
HIV
Western blot tests detect antibodies
to the HIV virus in the blood. Both tests
must be positive to confirm an HIV
infection. Antibodies are proteins made
by the body's immune system when it
detects harmful substances, such as the
HIV virus.
A complete blood count (CBC)
and white blood cell differential may also
show abnormalities.
Persons with AIDS usually have
regular blood tests to check their CD4
cell count. CD4 cells are a type of T cell.
T cells are one kind of cell of the immune
system. They are also called "helper
cells." A CD4 cell count that is lower
than normal may be a sign that the virus
is damaging the immune system. (A
normal CD4 count is from 500 to 1,500
cells/mm3 of blood.)
When the CD4 count gets too low, the
risk of infections and some types of
cancer increases.
Other tests that may be done include:

HIV RNA level, or viral load, to

check how much virus is in the
blood
Pap smear to check for cervical
cancer
Anal pap smear to check for
cancer of the anus

Support Groups
Joining a support group where members
share
common
experiences
and
problems can often help the emotional
stress of having a long-term illness.
Outlook (Prognosis)
At this time, there is no cure for AIDS. It
is always fatal without treatment. In the
U.S., most patients survive many years
after diagnosis because of treatment
with
HAART.
New
medicines
are
continually being developed.
Possible Complications
When a person is infected with HIV, the
virus slowly begins to destroy that
person's immune system. How fast this
occurs differs in each individual.
Treatment with HAART can help slow or
halt the destruction of the immune
system.

Once the immune system is severely

damaged, that person has AIDS, and can
now get infections and cancers that most
healthy persons would not get. Doctors
have found that when CD4 falls below
certain
counts,
specific
types
of
infections and cancers can develop.
When to Contact a Medical Professional
Call for an appointment with your health
care provider if you have any of the risk
factors for HIV infection. Also call if you
develop symptoms of AIDS. By law, the
results of HIV testing must be kept
confidential. Your health care provider
will review test results with you.
Prevention
Preventing HIV/AIDS:
Do not use illegal drugs and do not share
needles or syringes. Many communities
now have needle exchange programs,
where you can get rid of used syringes
and get new, sterile ones. These
programs can also refer you for addiction
treatment.
Avoid contact with another person's
blood. If possible, wear protective
clothing, masks, and goggles when
caring for people who are injured.
If you test positive for HIV, you can pass
the virus to others. You should not
donate blood, plasma, body organs, or
sperm.
HIV-positive women who plan to get
pregnant should talk to their health care
provider about the risk to their unborn
child. They should also discuss methods
to prevent their baby from becoming
infected, such as taking medicines
during pregnancy.
Breastfeeding should be avoided to
prevent passing on
HIV to infants
through breast milk.
Safer sex practices, such as using latex
condoms, are effective in preventing HIV
transmission. But there is a risk of
getting the infection, even with the use
of condoms. Abstinence is the only sure
way to prevent sexual transmission of
HIV.
HIV-positive patients who are taking
antiretroviral medicines are less likely to
transmit the virus.
The U.S. blood supply is among the
safest in the world. Nearly all people

infected
with
HIV
through
blood
transfusions received those transfusions
before 1985, the year HIV testing began
for all donated blood.
If you believe you have been exposed to
HIV, seek medical attention right away.
Do not delay. Starting antiviral medicines
can reduce the chances that you will be
infected. This is called post-exposure
prophylaxis (PEP). It has been used to
prevent transmission in health care
workers injured by needle sticks.
Treatment
There is no cure for AIDS at this time.
But treatments are available to manage
symptoms. Treatment can also improve
the quality and length of life for those
who have already developed symptoms.
Antiretroviral therapy suppresses the
replication of the HIV virus in the body. A
combination of antiretroviral drugs,
called antiretroviral therapy (ART), also
known as highly active antiretroviral
therapy (HAART), is very effective in
reducing the amount of
HIV in the
bloodstream. This is measured by the
viral load (how much free virus is found
in the blood). Preventing the virus from
reproducing (replicating) can improve Tcell counts and help the immune system
recover from HIV infection.
People on ART with suppressed levels of
HIV can still transmit the virus to others
through sex or by sharing needles. With
ART, if the level of HIV remains
suppressed and CD4 count remains high
(above 200 cells/mm3), life can be
prolonged and improved.
HIV can become resistant to one
combination of ART. This is most true in
patients who do not take their
medications on schedule every day. Tests
can check whether an HIV strain is
resistant to a particular drug. This
information can be useful in finding the
best drug combination and for adjusting
the drug combination when it starts to
fail.
When HIV becomes resistant to HAART,
other drug combinations must be used
to try to suppress the resistant HIV strain
of HIV. There are a variety of new drugs

on the market for treating drug-resistant

HIV.
Treatment with ART has complications.
Each drug has its own side effects.
Common side effects are:
Collection of fat on the back (buffalo
hump) and abdomen
Diarrhea
General sick feeling ( malaise)
Headache
Nausea
Weakness
When used for a long time, these drugs
increase the risk of heart attack, perhaps
by increasing the levels of cholesterol
and glucose (sugar) in the blood.
Persons on ART are monitored by their
health care provider for possible side
effects. Blood tests measuring CD4
counts and HIV viral load will likely be
done every 3 months. The goal is to get
the CD4 count close to normal and to
suppress the amount of HIV virus in the
blood to a level where it cannot be
detected.
Medicines may be prescribed to treat
problems related to AIDS such as
anemia, low white cell count, and to
prevent opportunistic infections.
Epidemiologists have long established
beyond all reasonable doubt that
infection
by
the
human
immunodeficiency virus type 1 (HIV-1)
leads to the acquired immune deficiency
syndrome (AIDS). Natural history cohorts
have demonstrated that the median time
from infection to development of AIDS is
approximately 12 years, and that this
long duration is broadly similar in all
populations infected by HIV-1, in all risk
groups, in all ethnic groups and in all
geographical
areas.
These
epidemiological observations suggest
that
HIV-1
causes
AIDS
largely
independently
of
human
major
histocompatibility complex (MHC) and
HIV-1 sequence polymorphisms, as great
diversity of both these factors exist
world-wide. This is not to say that HLA
and HIV diversity do not affect the
natural history of HIV disease, but these
observations
support
a
common
mechanism of HIV-1 pathogenesis which
is largely independent of human and
viral diversity.

The genome of HIV-1 is small, less than

10 kb, and hundreds of full-length HIV-1
sequences have been studied. All nine
HIV-1 genes and their products are
characterised, mostly in great detail. The
molecular basis of viral entry and
tropism is known, and the humoral and
cellular immune responses to infection
characterised at the level of the
individual epitopes. Given that there is
greater understanding of the biology of
HIV-1 than for any other pathogen, it is
frustrating that the pathogenesis of HIV
disease is still so difficult to fully define
at a molecular level.
The essence of HIV-1 infection is a slow
decline in CD4+ T-cells over time, such
that once a threshold of approximately
200 x 109 CD4 cells/l is passed, immune
deficiency and virally-induced tumours
are increasingly liable to occur. It has
been known for 17 years that the
primary receptor for HIV-1 is the CD4
molecule, expressed on the surface of
mature
T-helper
lymphocytes
in
peripheral blood and lymph node, and
also on macrophages and dendritic
cells1,,2. More recently, the HIV-1 coreceptors have been defined as the 7transmembrane spanning chemokine
receptors, principally CCR5 and CXCR43
5. The distribution of these co-receptors
on
primary,
activated
CD4+
Tlymphocytes defines the tropism of HIV
in vitro, and almost certainly in vivo.
Only CD4+/CCR5+ T-lymphocytes are
infectable by primary HIV-1 isolates
taken directly from patients.
The
central
question
of
HIV-1
pathogenesis
is
through
what
mechanism does HIV-1 destroy CD4+ Tcells? Is the virus directly lytic for these
cells
through
infection
and
viral
replication, or is the mechanism indirect?
For example, are HIV+/CD4+ T-cells
killed through the action of HIV-specific
cytotoxic T-lymphocytes (CTLs),
or
through the action of toxic soluble viral
products such as gp120, or even through
induction of apoptosis leading to the
death of virally infected cells?
The loss of CD4+ cells begins during
primary HIV-1 infection, and continues,
not necessarily at a constant rate,
throughout the course of infection. In

late HIV disease, after the decline of

CD4+ T-cells to below 200 x 109/l, there
is some evidence that CD4+ cells decline
more rapidly. In this review, I shall focus
in turn firstly on primary HIV-1 infection,
secondly
the
chronic
phase
of
asymptomatic HIV infection and finally
on late HIV disease, and review the data
on the mechanisms affecting the loss of
CD4+ cells at these periods. The natural
history of HIV-1 infection is shown
diagrammatically in Figure 1.

Primary HIV infection

The early events of HIV infection are
likely to be important to the later course
of the disease, and are, therefore, the
most appropriate starting point to
consider pathogenesis. The very earliest
events in the entry of HIV-1 in vivo are
impossible to study in humans. Our
knowledge of the mechanism of infection
is
thus
mostly
inferred
from
experimental
infections
of
rhesus
macaques with SIVmac251. In this
model, animals can be sacrificed at
intervals after mucosal exposure in order
to determine the localisation of the virus
over time. As SIV shares a very similar
genetic structure to HIV and also uses
CD4 as the primary receptor, it is
probably a legitimate model for the
study of viral entry in vivo. However,
there is little evidence that mucosal
transmission is the dominant route of
transmission for primate lentiviruses in
natural infection. As with any animal
model, therefore, caveats as to exact
applicability to human disease must be
borne in mind.
After mucosal exposure to SIVmac251,
for example across the vagina of the
rhesus macaque, HIV-1 appears to first
infect
mucosal
Langerhans'
cells
(mLc)6,,7. These cells are migratory
within mucosa, and possess long
processes which interdigitate among the
mucosal epithelial cells, and thus submucosal Lc may be present on the
surface of epithelia. Langerhans' cells
are
a modified
macrophage,
are
fundamental to antigen presentation and
attract CD4+ T-cells to their dendritic
processes. Mucosal Lc weakly express
CD4 and CCR5, and hence are infectable
by HIV-18; however, these Langerhans'
cells also express a cell surface lectin,

DC-SIGN, which is capable of binding the

HIV-1 gp120 with a high affinity9. The
most plausible mechanism for infection
across a mucosal surface is that free
infectious virions are bound to DC-SIGN
on
the
surface
of
mLc,
which
interdigitate and migrate within the
vaginal mucosa. Virus bound to mLc is
then moved away from the mucosal
surface, and is brought in close proximity
to CD4+ T-cells. The DC-SIGN bound
virus is then able to infect CD4+/CCR5+
T-cells, and these infected T-cells then
migrate to their regional lymph nodes
(reviewed by Mascola10).
The
HIV-infected
T-cells
remain
sequestered in regional lymph nodes
until a threshold of replication is reached
within 26 weeks, following which a burst
of plasma viraemia occurs. This is
termed primary HIV infection (PHI).
Following PHI, virus is disseminated
within days throughout the body and
seeds local, peripheral and distal
reservoir sites. PHI is associated with a
very high plasma viral burden, and levels
of viral RNA detected by quantitative RTPCR may exceed 5 x 106 copies RNA/ml.
PHI may be accompanied by either
symptoms of a seroconversion illness,
comprising
rash,
painful
lymphadenopathy,
arthropathy
and
fever, or more often this period is
clinically asymptomatic. The viraemic
peak resolves spontaneously after 24
weeks, associated with a primary
immune response to HIV. Although
plasma viraemia is suppressed after
seroconversion,
HIV-1
is
never
eliminated and the HIV genome can be
found in T-cells in all subjects at all
stages of disease, and in varying
quantities as virion-associated RNA in
the plasma.
The viraemic peak of PHI is invariably
associated with a transient reduction in
CD4+ T-cells in peripheral blood. This is
generally modest and short-lived, but
may occasionally lead to a reduction of
CD4+ T-cells below 200 x 109/l, which in
turn may lead to overt clinical
immunosuppression. Indeed, cases of
opportunistic
infections
such
as
Pneumocystis carinii pneumonia and
oesophageal candidiasis have been
reported from this period of acute,
reversible immunosuppression. Once the

viraemic peak has been resolved, CD4+

cell levels return towards baseline levels,
but remain lower than that seen preinfection.
This observation of an acute loss of
CD4+ T-cells associated temporally with
the
rapid
appearance
of
plasma
viraemia, and the recovery of CD4 count
once the plasma viraemia is reduced,
would appear to support the capacity of
HIV-1 to directly kill CD4+ T-cells through
lysis. Certainly, high levels of primary
virus replication in activated peripheral
blood mononuclear cells (PBMCs) in vitro
can
lead
to
syncytial
formation
(multinucleated
giant
cells)
and
consequent cell death, and HIV-1 is
ultimately lytic in primary cell culture,
even if syncytia are not observed.
However, viraemic levels are higher in
PHI than at any other time in the course
of HIV-1 infection, and there is no
immune response against the virus at
PHI. It is possible, therefore, that the
transient reduction in CD4+ T-cells at PHI
represents the unopposed effect of high
level HIV replication, which is curtailed
by the immune response. Thus, the
direct viral cause of CD4 T-cell
destruction at PHI may not represent a
common mechanism throughout the rest
of the course of HIV-1 infection, when an
immune response is always present.
The initial viraemic peak falls to a set
steady state within several weeks or
months of infection, the level of which
varies considerably between individuals
and is predictive of prognosis11.
Coincidentally with the peak of viraemia
there is a vigorous HIV-specific immune
response
involving
cell
mediated
immunity, CD8+ CTL and CD4+ T-helper
HIV-specific responses, in addition to
antibody production, all of which are
believed to play an important role in
controlling the initial plasma viraemia.
The study of neutralising antibodies to
the autologous primary isolates at PHI
suggest that these are relatively slow to
develop, and are rarely detectable until 6
months after infection12. By contrast,
HIV-specific, CD8+, HLA-restricted CTLs
do appear to be related temporally to
the
reduction
in
viraemia13.
Furthermore, a number of groups have
documented the emergence of escape
mutations within CTL epitopes following

the immune response in PHI14,,15.

These observations have been taken as
evidence that CTLs are the major
effector of the immune containment of
HIV-1 following PHI. Certainly, it would be
attractive to consider that the slow
progression of HIV-1 disease is related to
the balance between viral replication
and the cellular immune response
mediated through CD8+ CTL. However,
other hypotheses exist for the control of
viraemia
at
PHI.
Following
the
appearance of the plasma viraemia, nonneutralising antibodies appear at the
same time as CTL, principally to the core
(p24), matrix (p17) and envelop (gp120)
proteins16.
These
non-neutralising
antibodies may bind to virions to
generate circulating immune complexes,
which are subsequently cleared through
Fc-receptor binding in the spleen, a
mechanism of viral clearance thought to
be relevant to enterovirusviraemia.
Furthermore, availability of activated
CD4+ T-cells may become limiting
during the viraemia of PHI; exhaustion of
the CD4+ substrate for HIV replication
may lead to reduction of viraemia
without an immune mechanism being
involved17. This hypothesis has some
experimental
support
from
the
observation that treatment with low dose
cyclosporin-A at PHI reduces T-cell
activation and leads to reduction in
viraemia and preservation of CD4
cells18.
When the immune system first responds
to HIV-1, the outcome is thought to
determine much of the subsequent
natural history of the disease. The titre
of the antibody response to p24 at
seroconversion
is
associated
with
disease outcome16. Acute primary
infection activates the HIV-1 specific
CD4+ T-helper response. However, this
HIV-specific CD4+ T-helper response is
generally lost during the course of
untreated HIV-1 infection. In untreated
patients with high levels of plasma
viraemia after PHI, the HIV-specific Thelper response is undetectable within
the first year of infection. When antiretroviral drugs are given 6 months or
later after seroconversion, HIV-specific Thelper responses do not return if already
lost,
and
cytotoxic
T-lymphocytes
directed against HIV continue to decline.
However, early anti-retroviral therapy,

during
PHI,
is
associated
with
preservation of both CD8+ CTL and
CD4+ T-helper lymphocyte responses to
HIV19. Most studies have failed to detect
HIV specific CD4+ T-helper responses in
untreated patients except for those with
very slow progression and low viral
loads20.
Summary
Primary HIV-1 infection is manifest by a
viraemic peak associated with a
temporally related decline in CD4+ Tcells; the viraemia is probably curtailed
by an HIV-specific CD8+ CTL response.
There is some evidence that the
reduction in CD4+ T-cells in PHI may be
a direct and unopposed effect of HIV-1
replication which is curtailed and then
controlled by cellular immunity.
Previous Section
Next Section
Chronic asymptomatic HIV-1 infection
As shown diagrammatically in Figure 2,
following PHI the CD4 count returns
towards baseline but does not regain
pre-infection levels. CD4 counts decline
slowly, and in a linear manner, during
the chronic asymptomatic stage of HIV-1
infection. During this period, HIV-1 RNA
levels as determined by RT-PCR are
highly variable between individuals, and
may range from <50 copies RNA/ml, to
>1,000,000 copies RNA/ml11. However,
HIV-1 proviral DNA is always detectable
in PBMCs, even if plasma viraemia is
undetectable. The small number of
infected cells in peripheral blood,
generally
1:50,000
PBMCs,
has
suggested that direct viral lysis is an
unlikely mechanism for the decline of
CD4 cells in this period of infection.
The breakthrough in the investigation of
the pathogenesis of CD4+ T-cell loss in
this period of HIV infection came from
careful multidisciplinary observations of
the effect of potent, combination antiretroviral chemotherapy. Use of antiretroviral drugs leads to suppression of
viral replication, a reduction of plasma
viraemia and an increase in CD4 count.
Two landmark papers from Ho and Shaw
revealed that starting anti-retroviral
therapy altered the steady state of HIV-1
replication, where viral replication and

clearance were in balance21,,22. The

drug therapy strongly suppressed viral
replication and lead to an exponential
decline in plasma viraemia over 12
weeks, followed by a slower second
phase
decline
after
24
weeks.
Mathematical modelling of the plasma
viraemia decay slope enabled the
production rate of HIV-1 virions to be
determined, as 107108 virions/day. The
rapid replication of virions is from within
the peripheral CD4+ T-cell compartment,
and leads to a greatly reduced T-cell life
expectancy of approximately 2436 h,
against an expected life-time in the
absence of HIV infection of 100 days.
The slower second phase decline
represents HIV-1 replication in long-lived
cells such as macrophages and dendritic
cells. The model also accounted for the
loss of CD4+ T-cells by assessing the
rate of CD4 turnover as 70-fold over
baseline, caused by the viral replication
within this compartment leading to
premature cell death.
These models of HIV dynamics and
pathogenesis have been termed the
bath-tub analogy. The loss of CD4+ Tcells is the result of greatly increased
turnover through HIV-1 driven CD4
death; new CD4+ T-cell production fails
to match the increased CD4 cell loss,
and hence a slow, continuous reduction
in CD4 cells is seen. As with a bath-tub,
the level of water can be maintained if
the taps are on full, even if the plug is
out. However, over time the taps will fail
to keep up with the rate of water going
down the plug, and a gradual loss of
water level will be observed, until the
bath is nearly empty.
There have been a number of objections
to
this
simple
model
of
HIV
pathogenesis. Firstly, Miedema's group
studied the telomere length in CD4 and
CD8 lymphocytes from HIV-infected
subjects23. Telomeres are repetitive DNA
sequences
at
the
end
of
all
chromosomes which are cut by about 50
bp with each cell division. Although there
is an enzyme which can re-extend
telomeres (telomerase), the enzyme is
only expressed in germ cells and
tumours. Hence, telomere length should
be an estimate of the number of times a
cell has divided. Miedema showed that
there was telomere shortening in HIV

infection, but that it occurred in CD8+

cells, and not in CD4+ cells. He
concluded that there was evidence for
increased CD8+ cell turnover in HIV
infection, but no evidence for increased
CD4+ turnover.
Subsequently, a number of techniques to
label lymphocytes in vivo have been
developed, using bromodeoxyuridine
(BrdU), [6-2H]-glucose or [13C]-glucose.
A summary of all these studies supports
increased turnover (26-fold) of both
CD4+ and CD8+ T-cells in HIV infection,
with a reduction in half-life of about 60%
compared to HIV-negative subjects
(reviewed
by
Johnson24).
The
mechanism for the effect of antiretroviral therapy on raising CD4+
lymphocyte counts could, therefore, be
either through reducing the rate of cell
death (as in the bath-tub model), or
through increasing CD4+ cell production.
Unfortunately, there are conflicting data
supporting both these hypotheses.
Interestingly,
studies
from
sooty
mangabeys,
an
old-world
monkey
species naturally infected with SIVsm, a
virus which is non-pathogenic in this
host, show that T-cell turnover is normal
in this model despite high levels of
plasma viraemia25. This observation, if
reproduced, would suggest that indirect
mechanisms for T-cell loss are more
likely to account for the observations in
HIV-infected subjects.
The unexpected,
but reproducible,
observations that CD8+ lymphocytes
have a higher turnover and shorter halflife in HIV-infected subjects re-focuses
attention on the role of CTL in HIV
infection. Potent drug treatment in
chronic asymptomatic infection produces
impressive restoration of immunity as
judged by rise in CD4 count and loss of
disease
progression.
However,
distortions in the CD4+ repertoire are
not corrected and the HIV-specific CD8+
CTL populations decline. Although this
decline has been attributed to a loss of
antigenic drive, because potent therapy
is so effective at suppressing viral
replication, very early use of antiretroviral
drugs
preserves
CD8
populations at a low but easily
detectable
level
(reviewed
by
Siliciano26). Since it is becoming clearer
that there is on-going viral turnover even

in patients on continuous efficient

treatment, the decline in CD8+ numbers
may be attributable, at least in part, to
loss of HIV-1 specific T helper function19.
There is good evidence that the
preservation of CD8+ CTL function and
numbers in animal models is intimately
dependent on T helper function.
A synthesis of these data supports HIV
replication leading to loss of CD4+ Tlymphocytes both by direct (or indirect)
cell killing, and through the action of HIVspecific CTL killing of CD4+/HIV+ T-cells.
This would also account for the observed
increase in CD8+ T-cell turnover in HIV
infection, as the action of CTL killing also
increases the killing of the effector cells.
The relative roles of alterations in T-cell
production induced by HIV-infection and
anti-retroviral therapy require further
experimental study.
Summary
Chronic asymptomatic HIV infection is
associated
with
highly
dynamic,
persistent viral replication, with the
production
of
approximately
108
virions/day. Viral replication leads to loss
of CD4+ T-cells, which could be due
either to increased cell death, or to
reduced production, or both. The
increased turnover of both CD4+ and
CD8+ T-cells in HIV-1 infected subjects
compared to controls supports the killing
of virally infected cells by HIV-specific
CTL as a leading hypothesis for CD4+ Tcell decline in HIV infection. However,
the direct relationship between plasma
viral load and rate of CD4 decline
suggests that viral replication also
contributes, directly or indirectly, to CD4
loss.

Late stage HIV-1 infection

The decline in CD4 count during the
course of HIV-1 infection is not constant
over time. There is a very rapid,
transient decline in CD4+ T-cells at
primary HIV infection, as noted above.
The decline in CD4 count in the chronic
asymptomatic phase of HIV-1 infection is
variable, and related principally to the
steady state level of plasma viraemia.
However, the decline in this phase
appears to be approximately linear, and

hence constant over time. However, in

late stage HIV disease, when the CD4
count is < 200 x 109/l, there is evidence
of an increase in the rate of CD4 decline.
It was observed early in the HIV
epidemic that the phenotype of HIV-1
isolates grown from patients at different
stages of HIV infection were different.
Asjo and Levy showed independently
that viral isolates taken early in the
course of infection were slow growing,
producing
low
titres
of
reverse
transcriptase in culture (slow, low).
These isolates could grow in fresh
primary peripheral blood mononuclear
cells (PBMCs), but were not able to infect
transformed, immortalised T-cell lines
such as H9, CEM or MT227,,28. By
contrast, isolates made from patients
with advanced HIV disease were able to
grow rapidly to high titre in PBMCs and a
wide range of T-cell lines (fast, high).
Subsequently, Tersmette showed that
the viral phenotype could be defined by
the
ability
to
produce
syncytia
(multinucleated giant cells) in the MT-2
cell line; this allowed viral isolates to be
characterised as non-syncytial (NSI
slow/low) or syncytial (SI fast/high)29.
Fouchier then showed that the viral
phenotype NSI/SI could be defined
genetically through the charge of the V3
loop in the gp120 envelop30. Since the
discovery of the chemokine receptors as
HIV co-receptors, it has been possible to
understand these phenomena at a
molecular level.
NSI viruses are associated with primary
HIV infection and early chronic disease.
These viruses use CCR5 as their coreceptor. In late disease, viral isolates
use CXCR4 as their co-receptor, or have
dual tropism for both CCR5 and
CXCR431,,32.
CCR5
is
expressed
principally on activated T-lymphocytes
and macrophages, and is not highly
expressed on resting T-cells. This is part
explains the association between T-cell
activation and susceptibility to HIV-1
infection in vitro. By contrast, CXCR4 is
more widely expressed on resting and
activated immune cells. With the switch
in viral phenotype from NSI to SI, and
from CCR5 to CXCR4 usage, the capacity
exists for HIV-1 infection of a broader
range of target cells. Furthermore,
SI/CXCR4 viruses are more cytopathic in

vitro, and replicate to higher levels than

NSI/CCR5 viruses, which may lead in turn
to more efficient T-cell killing.
The difference between NSI/CCR5 usage
and SI/CXCR4 usage can be shown to
reside in 2 amino acid substitutions in
the V3 loop of gp120. The mutation rate
of HIV-1 is high, at 1:10,000 bases
substituted per replication, and as the
HIV genome is approximately 10,000
bases, and 108 virions are produced/day,
the capacity to generate the two
SI/CXCR4 mutations in V3 must occur on
a daily basis. Yet, throughout the course
of early and chronic HIV infection, it is
only possible to isolate NSI viruses.
Genetic studies of HIV+ subjects who
have died from unrelated causes during
this period show no evidence of
SI/CXCR4 mutations. If these SI/CXCR4
mutations are being generated, then
they are strongly selected against in
favour of NSI/CCR5 using envelopes32.
One hypothesis for the continued
selection of NSI/CCR5 viruses is that the
SI/CXCR4 mutations are under strong
cellular immune control. Thus, whenever
these mutations appear, the dominant
immune response against the mutant
form leads to maintenance of the
NSI/CCR5 form. In late HIV disease, the
loss of cellular immune regulation which
leads to AIDS also suppresses the
regulation of the SI/CXCR4 variants.
Thus, late stage HIV-1 infection may see
an increased rate of CD4 loss through
broadening
of
the
viral
tropism,
mediated by a switch in co-receptor
usage from CCR5 to CXCR4. Presumably,
CD4+ T-cell loss is this period of
infection is entirely mediated through
the direct (or indirect) effects of viral
replication, as there is no remaining
cellular immune response.
The critical role of the CCR5 co-receptor
in defining the entry of HIV-1 into
activated T-cells can be demonstrated
through
the
impact
of
CCR5
polymorphisms. A deletion mutation of
32 base pairs of CCR5 has been
described, -32, where the co-receptor is
synthesised but is unable to be
expressed on the cell surface33.
Subjects who are homozygous for the 32
mutation
appear
to
be
immunologically
normal,
yet
are

resistant to HIV-1 infection, at least by

NSI/CCR5
using
primary
isolates.
Approximately
1%
of
Caucasian
populations are homozygous for this
mutation,
and
17%
heterozygous.
Heterozygosity for -32 does not prevent
HIV-1 infection, but is associated with a
slower rate of CD4 decline, and hence a
better prognosis in HIV-1 infection34.
Other polymorphisms, such as in the
SDF-1 promotor region, also impact on
the rate of CD4 decline. Presumably,
these polymorphisms affect the relative
infectability of activated CD4+ T-cells,
and further support the central role of
viral replication in the destruction of
CD4+ lymphocytes.
Summary
The natural history of HIV-1 infection is
marked by a prolonged asymptomatic
period with a continuous slow decline in
CD4+ T-lymphocytes. While this period is
clinically quiet, the virus is highly
dynamic, with large numbers of virions
produced every day. The rate of CD4
decline is directly related to the quantity
of virus detected in plasma, suggesting a
direct
relationship
between
viral
replication and CD4+ T-cell destruction.
A direct viral T-cell killing mechanism
may indeed be dominant in the absence
of an effective cellular immune response
to HIV-1, as seen prior to seroconversion
(primary HIV infection) and at late stage
disease
when
HIV-specific
cellular
immunity is exhausted. However, during
the chronic asymptomatic phase of HIV-1
infection, which is characterised by an
active HIV-specific humoral and cellular
immune response, turnover of both
CD4+ and CD8+ T-lymphocytes is
elevated. The most plausible explanation
for this is that HIV-specific CD8+ CTL are
the main effectors of HIV+/CD4+ T-cell
destruction.