Download Human Immunodeficiency Virus and HIV Disease

Human Immunodeficiency Virus and HIV Disease
Retroviruses-Some History
Retroviruses
Genetics of HIV
Types of HIV-1
Natural History of HIV
Infection
How HIV Infects a Cell
Transmission Rates for HIV
Opportunistic Infections
According to the World Health Organization, every 5.8 seconds a person is newly infected with HIV and every
10.5 seconds someone dies of AIDS.
Retroviruses-Some History
HIV is the abbreviation for Human Immunodeficiency Virus. There are two main forms of HIV retrovirus:
HIV-1 and HIV-2. HIV-1 was discovered by Luc Montagnier and his associates at the Institute Pasteur in Paris in
1983. HIV-2 was first identified among patients in Senegal in 1986, where it remains endemic, although it has
spread to other previously Portuguese colonies in Africa and to Europe. HIV-2 is much less virulent (five to eight
times less transmissible and usually taking 12 to 14 times longer to reach full blown AIDS)1. A person can be
infected with both HIV-1 and HIV-2 at the same time.
Although the AIDS epidemic sprung unannounced upon the world in the early eighties, the oldest verified case
dates back to 1959 in Zaire. A blood sample of an anonymous man was discovered in the archives of a Zairian
(which was then called Congo) sexually transmitted disease (STD) clinic in Kinshasa and analyzed in 1998 to
establish its primacy. On October 1, 2008 another tissue sample dating from 1960 was announced. Using extremely
sensitive PCR technology, the authors conclude that these two samples had evolved from a source that was at least
50 years old, hence HIV originated no later than sometime during the start of the twentieth century—sometime
between 1884 and 1924.
The results of a backtracking the evolution of the retroviral genome of HIV-1 using complex mathematical
models allowing for both constant and variable rates of evolution was done on the available data by Bette Korber
and her associates. The group’s analysis required the use of parallel supercomputers to backtrack the evolution to its
source from monkeys2 (the chimpanzee species, Pan troglodytes troglodytes, to be exact, which carries the Simian
Immuno-deficiency Virus, SIV). The proposed model correctly placed the genome of the 1959 case on its computed
evolutionary tree. The analysis suggests that may be as many as eight disparate starting points for the disease. There
is an alternative analysis that puts the origin of HIV-1 somewhere between the years of 1590 and 1760, although the
disease may have erupted, died out, and re-erupted several times since then.
A 2002 paper reported the first chimp in the wild to have been found to have an SIV infection. The research was
based on analyses of fecal samples.
HIV-2 has been traced to the version of SIV carried by sooty mangabeys (but it does not cause illness among
them because of a special protein they have in their bodies). In fact, the genetic sequences of the two viruses HIV-2
and SIV are more alike than those of HIV-1 and HIV-2. In 2001, Beatrice Hahn and Eric Delaporte reported on
cross-species infections. They documented nine cases in which chimpanzees, sooty mangabeys, and a mandrill
passed SIV to humans. Antibodies to SIV were found in the victims’ blood samples. They also analyzed blood
samples of nearly 400 monkeys and baboons to assess the degree to which their antibodies bind to HIV. 18% of the
samples exhibited strong binding and another 14% showed less strong binding.
Another group of researchers followed a Cameroonian troop of sooty mangabeys and found that 64% of them
were infected with SIV. Perhaps more frightening, tests on primate handlers at zoos and animal research laboratories
found 14 of 418 people (3.3%) tested positive for Simian Foamy Virus, SFV. A search of stored blood samples
showed infections in asymptomatic workers as far back as 26 years! This result seems to indicate the very strong
possibility of further animal to human transmission of retroviruses!
Lest you think that retroviruses are fairly new to the scene, research into the Human Genome Project has
discovered that about 5% of our DNA contains pieces of ancient retroviral parts and these parts seem to be essential
to the development of a fetus.
1
It is also very rare in this country. As of 01/01/00, there were a total of only 94 cases recorded, 66 of which were born in West
Africa.
2
There seems to be a direct relation to hunting and butchering nonhuman primates and other mammals and the transmission of
infectious diseases, ranging from monkeypox to Ebola hemorrhagic fever to HIV. Keeping some primates as pets may also be a
source of transmissible disease. By the way, neither of these practices are at all rare in Africa today. Surely, they will continue as
long as it takes less effort to obtain a kcal of energy by hunting than by working to purchase food. Of course, our own country
began as a nation of hunters rather than cattle raisers, i.e., bushmeat is as American as apple pie.
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Several naysayers have claimed that HIV-disease either originated or was extended by the purported use of
African green monkey kidneys to cultivate Kaprowsky’s CHAT polio virus vaccine3 in the late 1950s and early
1960s. Edward Hooper raised these issues in his book The River published in 1999. Korber’s analysis shows
Hooper’s argument of origin to be a very low probability event, hence quite unlikely to be valid. Samples used for
constructing the CHAT vaccine held at the Wistar Institute have been analyzed and no trace of HIV or SIV was
found to be present. Whether or not HIV was extended by the immunization program remains to be conclusively
decided.
It had been suggested that the near universal use of injection drugs and reuse of nonsterile syringes beginning in
the 1950s likely enhanced the spread of many infectious diseases, of which HIV may very well have been one. This
proposal has also been refuted and most of the transmission of the disease in Africa has been determined to be
sexual.
Retroviruses
HIV is a special type of RNA virus called a retrovirus. Not all RNA viruses are retroviruses, e.g., the measles
virus and flu virus are RNA viruses, but not retroviruses. There are currently twelve families of retroviruses, some of
which are: mammalian type B, mammalian type C, avian type C, type D, BLV-HTLV, lentiviruses (slow viruses, of
which HIV is one), and foamy viruses or spumaviruses (which are not known to cause human disease, about which
much less is known, and for which humans have tested positive).
There are also retroviral infections of animals, e.g., SIV (simian immunodeficiency virus) infects nonhuman
primates, FIV (feline immunodeficiency virus) affects cats, BIV (bovine immunodeficiency virus) affects cows,
EIAV affects horses, CAEV affects goats, and the visna virus infects sheep.
The distinguishing feature of all retroviruses is that they are “backward,” as follows:
RNA→ ssDNA (single strand DNA) → dsDNA (double strand DNA) → RNA→ Protein Synthesis
c
d
e
f
using the enzyme complex reverse transcriptase in steps c and d. The first two steps of this process have no
error-correction mechanisms, hence are subject to frequent mutations.
There are only four known enzymes found inside an HIV retrovirion: HIV reverse transcriptase, HIV
integrase, HIV protease, and HIV RNase. Reverse transcriptase is found nowhere in an HIV-uninfected human
body.
Genetics of HIV
The HIV genome contains nine genes4 made of 9749 base pairs. All retroviruses contain the genes gag (codes
for internal structural proteins and capsid proteins using about 2000 base pairs), pol (codes for the three enzymes
necessary for replication using about 2900 bp), and env (using about 1800 bp, codes for the surface proteins gp120
and gp41 that protrude from the lipid envelope and attach to cellular receptors). Other genes within HIV are tat
(transactivator protein), rev (regulator of expression of virus protein), vif (virus infectivity factor), nef (historically
misnamed negative regulator factor, but really an enhancing factor), vpr (virus protein R), and vpu (virus protein
U).
The human cell acts to silence the genes of intruders to the system and the HIV gene tat works to prevent that
silencing.
3
4
At that time, there were three competing polio vaccines designed by: Salk, Sabin, and Kaprowsky.
SIV has ten genes.
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The HIV genome
The term gp# stands for glycoprotein of molecular weight # kiloDaltons. p# is a protein of molecular weight #
kiloDaltons. Thus p17 is a protein of molecular weight 17,000 Daltons. Compared to most drugs, these proteins are
absolutely massive molecules. Nevertheless, they are smaller than antibodies.
The gp120 connected to the gp41 stem is collectively called gp160 and it is this protein that must connect to the
CD4 receptor, together with other coreceptors, of T helper cells and macrophages. There are about 75 gp160 spikes
on each virion. p24 is found both on and within the capsid. The immune system preferentially perceives the
carbohydrate in the glycoprotein, thus overpowering the presence of the protein. This effectively shields the virion
from the immune system’s initial onslaught.
Types of HIV-1
Cells that use DNA to replicate are relatively stable and do not readily mutate because the double strand DNA
carries its own error-correcting mechanisms. But, retroviruses follow a longer, backward path and they can mutate
easily. In fact, they mutate about one million times more frequently than organisms using DNA. Retroviruses and
HIV, in particular, contain no good mechanism for error-correction. It is claimed that reverse transcriptase, which
governs part of this reaction, introduces a mutation an average of once in every 5000–10,000 nucleotides; that’s one
or two mutations per replication cycle for HIV. Successive generations of viral progeny occur, on average, every 2.6
days. That’s an average of 140 generations per year. Thus, the HIV that infected a person is not very likely to be the
same virus that they are infected with one or two years later.
Most random mutations affect the env gene, producing different envelope glycoproteins within a given
individual. Some HIV strains cannot infect certain cell lines. For instance, some variants can enter T cells but not
macrophages and vice-versa.
The HIV variants are divided into three groups: M, for major, N5, and O, for other or outlier6. Within the Mgroup there are at least ten subtypes or clades: A, B, C, D, E, F, G, H, I, J, and K. The B-clade is dominant in US,
5
In the September 1, 1998 issue of Nature Medicine, F. Simon announced the discovery of this variant of HIV-1 that fits neither
the M nor O groupings. It seems to fall between the M-group and the simian immunodeficiency virus, SIV. This is the N-group.
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Europe, Southeast Asia, and South America. Clades C and E dominate in Asia and A, C, and D dominate in Africa.
Each of the five clades differs from each other by as much as 35%.
A summary of the geographical distribution of the M-group HIV-1 subtypes is given below.
Clade
B
C
D
E
Occurrence Location
US, Europe, South America, Southeast Asia, Australia
Asia, Africa, India
Africa
Asia
Group O contains about thirty subtypes found mainly in West African countries such as Cameroon, Gabon, etc.
It has much higher prevalence than the N-group, but much lower than the M-group.
As far back as 1999 there were many reports of the existence of so-called recombinant strains of HIV. These
strains are combinations of the standard subtypes and many are resistant to various medications used to treat HIV
disease. Subsequent research has validated their existence and traced their spread. 2001 saw the publication of
research indicating that as many as 14% of new infections are recombinant. In 2002 there was a report of a patient
whose immune system had kept his HIV infection in check until he was infected with a second, different strain that
overwhelmed his resources.
Some researchers had claimed that the recombinant strains are not as hardy as the so-called wild strains.
Unfortunately, recent research shows that is not the case. Although wild type viruses are initially less virally fit, they
quickly evolve, becoming more fit and capable of causing significant disease.
The distribution of AIDS cases in the US peaked in 1997, decreased for two years, and held steady since then.
The numbers broken down by census group is somewhat troubling.
Racial Group
African-American
Hispanic
Caucasian
Other
% AIDS Cases
53
13
32
2
% General
Population
14
12
70
1
Clearly, people of color—blacks in particular—are inordinately affected by this disease.
About 10% of HIV-infected people progress to AIDS within a mere 2 or 3 years of infection (rapid
progressors). About 60% of HIV-infected adults/adolescents will progress to AIDS within 12–13 years (slow
progressors). About 5–10% of those infected will be symptom-free with stable T4 cell counts after 8 to 15 years
(nonprogressors). 10–17% will be AIDS-free after twenty years. It has been shown that nonprogressors have a
stronger cytotoxic T cell response to the virus. This seems to occur in two ways: there is a slightly higher CD8+
count and each cytotoxic T cell produces more perforins that attach to infected cells. There is also a small group of
what are called viremic controllers. These are people who test positive for HIV, but their immune systems keep the
virus at a very low level.
The Centers for Disease Control and Prevention provide the following graphs of the number of virions per
milliliter and CD4 counts per mm3 as a function of time for each of the three groups.
The first discovered case occurred in a woman in Cameroon and all tests with EIA or Western Blot were negative! There have
been only five such cases reported as of 10/2000.
6
This nomenclature is in the process of being revised.
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For more about these graphs, see the next section.
One study indicates that the presence of CCR2 receptors seems to be associated with nonprogression.
HIV evolves within the body of an infected person. Initially, most HIV is M-tropic, meaning that it favors
infection of macrophages as it binds to CD4 and the coreceptor CCR5. Macrophages that have been infected seem
to lose their cell death programming mechanism and continue to function for very long periods; some would even
say they become “immortal.” The virus then enters a middle phase where it is dual tropic and its envelope protein
gp120 can bind to the receptors CD4, CCR5, CXCR2, CXCR3, and, most especially, CXCR4; all of which are
found on T helper cells. Eventually the virus becomes T-tropic and shows a preference for T cells. Research
published in April of 2005 has determined that within days of infection, HIV destroys at least half of the CD4+ T
memory cells that could be used by the body to fight the infection.
HIV can attach to the CXCR4 coreceptor that is present on CD8+ cells, so it can also attack T cytotoxic cells,
which have a lower concentration of CD4 than T helper cells.
It has also been shown that HIV can hitch a ride on B cells, but not infect them. This ride takes the virus into the
lymph nodes where it can attach to follicular dendritic cells and then to T cells. One report found that HIV can
survive for as long as nine months on dendritic cells in a mouse model and at least 25 days in human tonsil tissue. At
these late dates the virus was still infectious. This helps to explain the viral rebound during so-called “drug holidays”
or, more technically, Structured Treatment Interruption (STI).
The National Institute of Allergy and Infectious Disease (NIAID) scientists have suggested that macrophages
can continue to produce new virions even after other CD4+ cells have been depleted. This makes macrophages
another reservoir for the virus.
Researchers also have noted disruptions in the sleep cycles of people infected with HIV. In vitro experiments
have implicated the protein Tat as a toxin for certain brain tissue that controls the body’s circadian rhythms.
Some people, mostly of north European ancestry, have mutations in the genes that code for CCR5. When the
deletion mutation, called ∆32 and read “delta-32,” occurs in the gene on only one of the two human chromosomes,
called a heterozygous mutation, the ability to be infected by the B clade variant of HIV that uses the CCR5
coreceptor is reduced by about 70%. A homozygous mutation, occurring on both chromosomes, greatly reduces the
infective ability, so much so that some of these people seem to be almost completely resistant to infection by this
form of HIV7. Another mutation that changes the form of CXCR4 to CXCR4 3′ UTR has been shown to lead to a
condition similar to long-term nonprogression. Only 1% of the whites of European ancestry are ∆32-homozygous
and it appears to be entirely absent in Japan and Central America. About 1% of Caucasians of northern European
ancestry are ∆32-heterozygous. Unfortunately, with good news comes bad news. The results of a study of people
with this homozygous deletion who were also infected with hepatitis C found that such patients had much higher
7
Such people do not have any intrinsic resistance to infection by a CXCR4 variant of HIV.
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levels of hepatitis C virus, HCV. Among the group infected only with HCV, there was a “striking increase”
(anywhere from a factor of 3 to a factor of 7) in the proportion with the homozygous ∆32-deletion. This seems to
indicate that this genetic mutation can lead to an increased risk for HCV infection and a worse outcome, to boot. On
the plus side, some research has found that people coinfected with the hepatitis-5 virus (GBV-C) seem to show an
improved survival rate, but other studies found no such benefit. Also, those affected by Type I diabetes tend to
manifest the disease later than those without the ∆32-deletion. A similar result seems to hold for the onset of
concomitant diseases for Type II diabetes patients.
One theory held that this genetic deletion had occurred about 700 years ago, making the global Plague
pandemic of the Middle Ages a possible candidate as the cause. Further research showed that infection by Yersinia
pestis does not use chemokine receptors, thus refuting this theory. Later work showed that myxoma virus, and likely
also the closely related smallpox virus, gain entry into cells by using the chemokine receptors on the cell surface.
Thus, the latest thinking is that ancestors of survivors of an ancient smallpox outbreak seem to have inherited a
resistance to HIV infection!
Natural History of HIV Infection
The natural history of HIV infection follows these six stages: Initial Infection (lasting 3–6 weeks), Acute HIV
Syndrome (lasting 1 week–3 months), HIV-Specific Immune Response (1–12 weeks), Clinical Latency (10
years, median), AIDS-Defining Illnesses (2 years on average), and Death.
After initial infection, 40–70% of patients enter the acute stage and develop flu-like or mononucleosis-like
symptoms, which may include fever, headache, sore throat, erythematous rash (looks like sunburn), diarrhea, and
generalized lymphadenopathy (severely swollen glands).
T4 cell counts, measured in the number of cells per microliter = µL = mm3, rise at first as the body mounts an
immune defense, but then fall. The CD4/CD8 ratio, normally about 2:1, drops to about 0.5 or less. The acute illness
usually resolves spontaneously within 2–3 weeks. It is during this initial infection that the disease is most readily
transmitted.
Much work indicates that during the acute phase the virus not only passes through the blood and lymph
systems, but it also seeds so-called latent reservoirs. Such reservoirs provide hiding places in which the virus may
be protected from most medications. In these latently infected cells, the HIV genome is integrated into
transcriptionally inactive regions of DNA called heterochromatin.
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Graph of the CD4+ count and viral load as a function of time. From the onset of
infection until the beginning of the HIV-specific immune response, at the initial
peak of the viral load curve, is the "window period." What follows is a period of
clinical latency. Once the CD4+ count falls below 300-400, constitutional symptoms
appear. Once the CD4+ count falls below 200, the person is officially an AID patient.
The human body takes anywhere from a few weeks to several months to mount a humoral immune response to
HIV (that’s slower than to other pathogens). This time is called the “window period” for the disease. Only after
(but not before) the HIV-specific immune response sets in, will most testing show positive results, meaning positive
for antibodies to HIV. This transition is called seroconversion, because only then can antibody be detected in the
blood. During the clinical latency that follows, there are few, if any, symptoms. The T4 cell count may return to the
normal range of 800–1200/µL, or it may stabilize at a lower level, or decline slowly. The number of virions in the
body approaches an equilibrium value, called the set point, at which the immune system is able to keep the virus
from replicating completely out of control. Despite the apparent lack of symptoms during this period, the virus is
active in the lymphoid system, where it is replicating like mad and destroying T cells like there’s no tomorrow—as
many as ten billion killed per day! The body continues to fight the good fight until it has exhausted its resources and
the T4 cell count continues to decline.
HIV-infected T cells have been shown to secrete an enzyme that converts a certain protein— known to keep the
brain healthy—into a brain-degrading chemical that can, at later stages of the infection, lead to dementia, seizures,
and other conditions.
Once the T4 cell count drops below about 400, constitutional symptoms appear, such as fever, weight loss,
fatigue, night sweats (strong smelling and profuse), diarrhea, and persistent generalized lymphadenopathy. Then
infections set in, such as oral and vaginal candidiasis, oral hairy leukoplakia, herpes zoster (shingles), herpes
simplex, and listeriosis.
As the T4 cell count continues to fall below 200, other opportunistic infections (Pneumocystis jirovecii
pneumonia when CD4+ < 200, mycobacterium avium complex, Kaposi’s sarcoma, candidiasis, coccidioidomycosis,
cryptosporidiosis, cytomegaloviral infections when CD4+ < 15, toxoplasmosis of the brain, HIV encephalopathy,
etc.) ravage the body until one or more of them cause death. HIV does not kill the patient. For the most part, the
opportunistic infections are the villains. More specifically, 90% of AIDS patients die of opportunistic infections, 7%
die of cancers8, and the remainder die of other causes.
For epidemiological purposes the CDC defines the onset of AIDS for an HIV+ person as that time when the
CD4 T cell count first falls below 200 or 14% of lymphocytes. Since this definition is strictly for epidemiological
purposes, once a person is classified as an AIDS patient, they are always classified as an AIDS patient, no matter
how high their CD4+ count may go at a later date, even after taking medications.
A great deal of research has strongly indicated that the extent of the acute Primary HIV Infection (PHI) is an
indicator of the time to development of AIDS. The more serious the PHI, the shorter the time to AIDS. Some argue
that this is “proof” of the need for early drug interventions. At least one paper found evidence of accelerated
8
HPV-16 is very strongly associated with oral cancer whether a person is HIV+ or not.
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progress toward AIDS for pediatric patients with a concomitant cytomegaloviral infection. Despite this argument for
early treatment, current thinking holds with a later onset of treatment—when the CD4+ cell count falls below 350.
HIV patients are more likely to become infected with Mycobacterium tuberculosis (MTB) and conversely,
MTB worsens the immunodeficiency of an HIV infection.
A clinical marker for infection is, ideally, a measure
(a) whose increase/decrease is highly correlated with progression of the disease,
(b) whose decrease/increase is associated with remission of the disease,
(c) which mirrors the effects of successful treatment, and
(d) is (relatively easily) measurable.
CD4 counts were the initial clinical markers on which all clinical decisions were based. Unfortunately, CD4 counts
are highly variable. They can vary from lab to lab, change during the course of a day, and vary as someone smokes
or doesn’t before testing. The best current clinical marker for the development of AIDS is the viral load; lower viral
load is better and higher is not good. Viral load or viremia is measured in copies of viral RNA per milliliter (mL).
Typical high values of the viral load are in the tens of thousands to as many as millions, while low values are below
2000 copies per mL. Values below 500 are called undetectable.
A problem with using viral load as a disease marker is that only about 2% of the immune system cells are
circulating in the blood stream at any one time. It would seem that much of the dynamics of infection is unavailable
for this form of indirect study.
From the onset of infection, HIV is reproducing at an extraordinary rate. In the early to intermediate stages, the
immune system can mount a defense that keeps the virus in check at its set point. The virus’s replication rate is
higher in the lymph nodes than in the plasma. In fact, 98% of the virus is in lymphoid organs. After years of battling,
the immune system starts to deteriorate and the body moves into the downward spiral of the disease.
A bare-bones history of an HIV infection.
The progression to AIDS has been characterized by an increase in immune activation about six months prior to
onset. The change to more rapid increase in viral load, called the inflection point, occurs about 18–30 months
before AIDS. One chemical marker, tumor necrosis factor-II, increases about 3.5 years before immune collapse.
You should notice that the viral load is highest during the acute stage of infection and endstage AIDS. In fact,
transmission during early primary HIV infection can occur as early as seven days before the onset of acute retroviral
syndrome. The notch in the CD4+ curve before the maximum of the viral load is where the body mounts an HIVspecific immune response, thus driving down the viral load. Then follows the period of clinical latency. As the
immune system is destroyed, the virus rebounds and constitutional symptoms and opportunistic infections follow.
How HIV Infects a Cell
Before the HIV virion can infect a cell, it must find it; not a trivial task given the maze surrounding each cell.
Though the main target of HIV is the class of T helper cells, most of these cells occur in a resting state and are
protected by an extremely powerful immune barrier consisting of a lightweight protein. Only when the resting T
cells are activated can they be infected because at that moment, the lightweight proteins are combined into a heavy
version, which is susceptible to the virus.
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Many protein microtubules penetrate the lipid bilayer of the cells and the virions attach themselves to a protein
called dynein9, which is referred to as a molecular motor that drives the particle toward the cell membrane. Once
there, HIV follows these steps as it infects cells and reproduces.
(1) Attachment of the virion to the receptor on the cell. HIV initially rapidly invades and replicates in gut
associated lymphoid tissue (GALT). Soon thereafter the virus has depleted the gut of T4 cells. It has been found
(2/2008) that the protein integrin alpha 4 beta 7, whose natural function is to direct T cells to the GALT, is also a
receptor for HIV. The following picture shows (artificially colored red) virions on the surface of a (green-colored)
T4 cell. This produces a natural joining of two neighboring cells allowing the virus to affect two cells at the same
time. To get to the T4 cells, HIV, its gp120 attaches to a T4 cell’s, or macrophage’s, CD4 receptor and the
coreceptor CCR5 and/or CXCR4 = fusin10.
Red HIV virions on a green-colored T cell
(2) Fusion with the cell membrane. The following diagram illustrates this process. The receptors from the virions
lock on to those of the cell (b). Then the virus receptors pull back (c) and forces a contact with the cell membrane
(d).
(3) Penetration of the cell membrane,
(4) Uncoating, whereby the virion sheds its coat and leaves its envelope behind.
(5) Reverse transcription of ssRNA to ssDNA using the enzyme reverse transcriptase occurs within the capsid.
(6) DNA synthesis of a second strand to form dsDNA.
(7) Migration of the viral genome to the nucleus of the cell. The distance it must travel is about 500 times its size as
it moves through the crowded interior of a cell until it reaches the nucleus. The genomes again hitch a ride on
the protein dynein as it follows the microtubules within the cell, moving from tube to tube in a journey that
could take as long as two to four hours.
(8) Integration of the viral genome into the host nucleus using the enzyme integrase. The integrated DNA form of
the virus is called a provirus.
(9) Viral transcription. Once the viral genome is within the host cell’s nucleus, HIV integrates its genetic material
into that of the host and henceforth, the host cell can become a virus factory. The cell could lie dormant (non-
9
McDonald and Hope, in a paper published in the November 11, 2002 Journal of Cell Biology, have developed a technique for
dyeing single molecules. They used this to follow the journey of the uncoated virion.
10
It has been hypothesized that gp41 binds to the host cell’s IL-2 (interleukin-2) receptor. This incites the host immune system to
attack IL-2. AIDS patients usually have antibodies to IL-2.
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replicating) for some time or it could immediately begin producing more viral RNA. Such dormant cells are
usually T memory cells and are called resting cells.
(10) RNA nuclear transport moves the RNA out of the host nucleus toward the inner surface of the cell membrane.
(11) Protein synthesis, whereby long proteins are split into smaller pieces, using the enzyme protease.
(12) RNA packaging and virion reassembly using the split proteins.
(13) Reencapsidation of newly made proteins and viral genome.
(14) Viral proteins push against the cell membrane and begin budding.
(15) Release of virions by either budding (see the pictures below, which were taken from a September 1998 issue of
the New England Journal of Medicine) or cell lysis.
HIV virions budding from the surface of a CD4+ cell; far view and near view.
The half-life of this processing of HIV into mature virions is about 90 minutes. Each infected cell can produce
an average of 250 new virions by budding before it fails and dies.
HIV also has the capacity to release its gp120 once it attaches to a T cell. This fills that receptor site on the T
cell and disables its immune function. Thus, even non-HIV-infected T cells can feel the negative effects of the virus.
After the initial infection, the virus favors lodging in the follicular dendritic cells of the lymph system. In
addition, the virus can hitch a ride on the dendritic cells present in the mucosa (in particular, the anal, vaginal, and
oral mucosa), using a receptor designated DC-SIGN, without infecting the cell. These cells also migrate to the
lymph nodes, carrying the virus in the style of a “Trojan horse.” This migration adds several days to the virus’s
infectious lifetime. Once there, the virus attacks the T4 cells that are not too deep into the lymph nodes.
There are two types of T4 cells: permissive and nonpermissive. Nonpermissive cells do not allow HIV
replication, while permissive cells allow such replication, even without the presence of the gene Vif. Current work is
searching for a method to make all T4 cells nonpermissive.
After an extended period of fighting the virus, the body succumbs and the dendritic cells in the lymph nodes and
B cells are “burned out.” For this reason, some people with advanced HIV disease do not produce antibody to the
virus. The following picture shows T cells (roughly spherical) on dendritic cells.
Ball-like T cells adhering to a dendritic cell
The virus can persist indefinitely (or so it seems) as latent proviral DNA, capable of replicating at any time.
There is a negative association between the activity level of cytotoxic T lymphocytes (CD8+) and viremia, the more
active the CD8+ cells, the lower the reproduction rate of the virus. On the other hand, HIV can infect CD8+ cells
without using either CD4 as a primary receptor or either of the coreceptors CCR5 or CXCR4.
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Research first announced at the Twelfth International AIDS Conference in Geneva, Switzerland (6/98) showed
that HIV can remain in resting (non-reproducing) T cells in the previously mentioned “latent reservoirs,” even after
intensive drug therapy. Later work (5/99) estimated that the half-life of these hiding places may be as long as forty
to sixty years! Scientists from the National Institutes of Health reported in January of 2001 that macrophages are
also likely latent reservoirs for HIV.
HIV basically does its dirty work by disabling the T4 helper cells, which are managers of the immune response.
It can also directly affect the cytotoxic or killer-T cells. HIV suppresses the production of CD4+ T cells, infecting
those cells and initiating apoptosis (one form of programmed cell death), and generally causing the cells to
malfunction. The website for cellsalive (www.cellsalive.com) shows the process of apoptosis, wherein the cell
begins to oscillate or bleb prior to lysing. Blebbing is an uncontrolled oscillation that eventually tears the cell apart.
A cell blebbing. At each stage the cell membrane becomes more unstable until lysis.
Since macrophages have some CD4 receptors, they too are targets for HIV infection. Once infected, their life
spans seem to be extended indefinitely (they become immortal). This is especially problematic because macrophages
can cross the blood-brain barrier. Hence, HIV has an avenue for attacking the brain, leading to AIDS dementia in a
high proportion (55–65%) of those infected11.
The B cells’ defense mechanisms do not work very well, because most of the virus is hidden away within the
CD4 cells and is unavailable for attachment by antibody. Some good news is that antibody b12 does block binding
by gp120.
HIV affects B cells with CD21 by coaxing them to produce excessive amounts of nonessential antibodies. They
then fail to respond to normal physiologic signals and are at increased risk of becoming cancerous.
It has been discovered that the tat protein in HIV acts as a chemoattractant of monocytes and dendritic cells.
Furthermore, basophils and mast cells exhibit CCR3 which HIV can use as a coreceptor, enhancing the production
of tat and improving viral replicability.
Strains of HIV, which use CXCR4 as the primary coreceptor, can also force the envelope glycoproteins to
induce syncytia formation, whereby healthy T4 cells fuse to one another in a group surrounding an infected cell.
This is a rather lethal form of the disease because it forces an abrupt drop in the CD4+ cell count and the resulting
rise in the likelihood of opportunistic infections. The syncytia-inducing (SI) version of HIV seems to be most often
found among intravenous drug users. It has been reported that syncytia are much more common than previously
thought. A research group was even able to visualize a moving syncytium consisting of thousands of cells. These
syncytia were short-lived, self-perpetuating masses that disrupted membranes made from collagen and punched
holes in endothelial tissue. Unfortunately, collagen is a major constituent of lymph nodes and blood vessels are lined
with endothelial tissue.
11
The older the HIV patient, the more likely there will be some form of dementia.
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11
T cells are clumping around single infected cells to form a syncytium.
It is known that as the CCR5 density on CD4+ cells increases, so too does disease progression. It has been
shown that HIV can even infect naive T cells, which do not divide.
Coinfection with herpes seems to put HIV replication on a fast track and hastens the spread of virus. In the same
vein, stress causes nerve cells to secrete norepinephrine and this seems to increase CCR5 density, CXCR4 density,
and increase the rate of viral gene expression. Taken together this means the virus spreads from five to ten times
faster than it might otherwise.
There is also the case of a superinfection, wherein an individual who is HIV+ is infected by a new strain of the
virus. This can accelerate the loss of T4 cells because the new strain can bypass the immune response developed to
suppress the original strain of the virus. It is even possible to be infected by several different strains, this can cause
collapse of the immune system and a rapid progress towards full blown AIDS.
Research published in November of 2006 [J Zheng, Y Xie, R Campbell, and others. Gp120-Independent HIV Infection of Cells
Derived From the Female Reproductive Tract, Brain, and Colon. J Acquired Immune Deficiency Syndromes 43(2): 127-136. October 1, 2006.]
showed that HIV could infect non-CD4+ cells. Such infection occurred in cell lines from the female reproductive
tract, brain tissue, and colon tissue, at rates of 0.36%-3.15% of cells; epithelial and brain cells were infected using
virions with and without functioning gp120; and neither CCR5 nor CXCR4 coreceptors were required for infection.
Transmission Rates for HIV
HIV is transmitted by exchange of bodily fluids via sharing contaminated syringes, vertical transmission from
infected mother to the child, and sexual contact. The main modes of transmission via blood or bodily fluids (in
rapidly decreasing likelihood of infection) are
1. transfusion of HIV-infected blood or infected blood products, (80-90%)
2. vertical transmission, from an HIV-infected mother to her baby, can occur during pregnancy, birth, and as a
result of breast-feeding12, (2-30%)
3. needle sharing among HIV-infected injection drug users, (0.3-30%)
4. injection with contaminated HIV-infected syringes, (0.3-30%)
5. piercing the skin with HIV-contaminated instruments in ear-piercing, tattooing13, and acupuncture, (0.35%)
6. sexual transmission with an HIV-infected partner involving the exchange of blood, semen, seminal fluid, or
vaginal fluids (0.3-30%)
7. needlesticks with contaminated needles and open cuts exposed to HIV-infected fluids (0.3-5%).
Since its discovery in 1983, no new modes of transmission of HIV have been discovered.
HIV cannot be transmitted by
ƒ shaking hands,
ƒ dry kissing,
ƒ sharing eating utensils,
ƒ insect vectors,
ƒ hugging,
ƒ across fomites.
HIV cannot be transmitted through
12
Cases of transmission when the infected mother pre-chewed her baby’s food have been recorded.
Tattoo artists should not only use sterile needles for each customer, but they should also use fresh supplies of ink. Dipping a
sterile needle into contaminated ink contaminates the needle!
13
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ƒ tears,
ƒ sputum,
ƒ saliva,
ƒ feces,
ƒ urine,
ƒ or emesis (vomit).
ƒ perspiration,
The infectivity of HIV illustrates the epidemiologic principle of the Host-Agent-Environment triad.
Transmission rates of HIV vary with the number of virions available for infection. Heterosexual transmission via
vaginal intercourse is enhanced because semen is highly alkaline in order to reverse the natural acidity of the
vagina—thereby protecting the incoming sperm.
Transfusion of tainted blood has an 80–90+% rate of transmission. In the past, blood products such as clotting
factors were made by pooling the blood from thousands of donors and then extracting Factor VIII. With the advent
of newer technologies, these clotting factors are made in the lab without using human blood.
Currently, blood supplies are screened for hepatitis, HIV, and other infections using the Nucleic Acid
Amplification Testing (NAT) technique. Consequently, the odds of infection in a randomly selected blood sample
are about one in 2,000,00014.
Injection drug use (IDU) and needle sharing has a transmission rate varying from a low of 0.3% to a high of
about 30%, depending on viral load, CD4 count, etc. Users who do not have access to sterile needles, should rinse
their works with tap water, shaking repeatedly, until no blood or other substances are visible. Then they should rinse
them with household bleach, shake the syringe, and rinse several times with water.
Vertical (maternal→ fetal) transmission is marked by several risk factors:
1. advanced clinical disease,
2. high viral load,
3. low CD4 count,
4. mode of delivery (vaginal (more likely) versus cesarean section (less likely)),
5. rupture of the membranes (the longer before delivery, the more likely there will be
transmission),
6. use of certain obstetrical procedures, such as episiotomy (an incision of the perineum to
prevent laceration and facilitate delivery),
7. poor nutrition (especially lack or excesses of vitamin A),
8. the presence of STDs, and
9. the lack of medical treatment for HIV-disease.
Recent estimates of global vertical transmission rates ranging from 10–30% and that fully 70% of that rate can
be attributed to the birthing process and the remaining percentage is due to blood exchange during gestation.
Vertical transmission in the US and Europe can been steadily decreasing because of the use of medications and
delivery by Caesarean section. The proportion of infections transmitted during the birthing process has plummeted
so much that in utero transmission has increased proportionately.
HIV-2 is rarely transmitted from infected mother to newborn child.
Once delivered, the child must face the risk associated with breast-feeding, which alone accounts for 10–20% of
the worldwide transmissions to newborns. C. Farquhar and colleagues report the results of a study of transmission
via breast milk in J Infect Dis 2002; 186:1173–1176. They found that higher levels of secretory leukocyte protease
inhibitor (SLPI), which is found in the saliva, were associated with decreased risk of transmission from mother to
child. How to increase these levels remains to be seen.
Several studies have shown that varying types of therapy using AZT and/or nevirapine can greatly reduce the
transmission rate from a high of 30% down to 5–8% or lower. Cesarean delivery can further reduce the risk, so
much so that on August 2, 1999 the American College of Obstetricians and Gynecologists recommended that all
HIV+ women be offered elective cesarean delivery at 38 weeks of pregnancy. Of course, this form of delivery
carries a much higher risk of other complications than a normal vaginal delivery. Accounting analyses indicate that
there is an overall (not necessarily per case) cost saving for cesarean deliveries. But, such analyses are not robust
with respect to deviations from the assumed probabilistic model, i.e., don’t bet the farm on their conclusions.
Children born to HIV+ mothers have “significantly worse cardiac function than other infants,” irrespective of
whether the infant is HIV+ or not15. It seems the HIV+ uterine environment is not as hospitable as was earlier
thought.
14
Even at such low odds, transmission can occur. Two recipients of blood from a donor infected a mere ten days before giving
blood contracted HIV disease in 2002. They represented the second and third such cases since the NAT test was instituted in
1999.
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The transmission rate via sexual intercourse varies from a low of 0.3% (1 in 300) to a possible high of 30% (1
in 3) when (a) the viral load is high (which occurs immediately after infection or in late stages of the disease), (b)
there are tears or lacerations in the surrounding mucosa, or (c) there are open sores on the genitalia of either or both
persons due to infection with other sexually transmitted diseases (STDs). An Australian theoretical study looked at
serodiscordant long-term gay male couples having unprotected anal intercourse with the infected partner having a
viral load of 10 and found the annual probability of transmission to be 0.014. In the same vein, in January of 2008
Swiss researchers published a study of such couples with the infected partner having a viral load of 40 and no
genital infections. The results indicated that there were no transmissions. Of course, these results may not have any
relevance in the poorest countries.
Globally, among the 128 countries that submitted data to UNAIDS, men who have sex with men, MSM, are 19
more likely to be infected with HIV than the general population. This is problematic because many of the countries
that have pledged to monitor the disease in at-risk groups ignore MSM.
For heterosexual transmission, women who transmitted the virus had four times the viral load of those that did
not, whereas men that transmitted had only one-and-a-half times the viral load of those that did not.
It has been shown that human sperm contains collegenase and spermine which start a breakdown of the
membrane that supports the colonic epithelium of the rectal mucosa. This causes a significant decrease in the natural
defenses and allows pathogens to more easily penetrate these tissues. Additionally, naturally occurring fragments of
the chemical prostatic acidic phosphatase form so-called amyloid fibrils that capture HIV particles and promote their
attachment to target cells, in particular CD4 T cells and macrophages. They also found that the fibrils, which are
termed semen-derived enhancer of virus infection (SEVI), can reduce the amount of virus needed to infect human
tonsillar tissue (1/2008).
Current knowledge is that unprotected anal intercourse is the most efficient method of sexual transmission16.
Recent research has shown that the number of virions in rectal secretions is much higher than originally thought
(even under antiretroviral therapy), thus putting the insertive partner at greater risk than previously suggested.
Although rare in the west, chancroid is a common sexually transmitted disease in many tropical developing
countries. It is a bacterial disease, caused by Haemophilus ducreyi, that accounts for more than half of all genital
ulcer disease in parts of Asia and Africa. The presence of this infection seems to upregulate CCR5 and CXCR4 in T
cells and macrophages, thus enhancing the likelihood of transmission of HIV17.
Other researchers have shown that the presence of herpes virus enhances the ability of HIV to infect epidermal
cells. This speaks to the transmission during oral sex. The best estimates before November 2002 for oral-genital
transmission were about 1 in 4500. Researchers at the University of California at San Francisco’s Center for AIDS
Prevention Studies followed 293 non-IV drug-using men whose only sexual contacts were oral sex with men. 98%
of the group participated in unprotected oral sex with a median of three partners in the previous six months. 28%
knew that their sexual partner was HIV+ and 39% admitted to swallowing ejaculate. None of those in the study
contracted HIV-disease. This translates to a zero percent transmission rate or at least one far lower than receptive
anal intercourse using a condom.
Much research has shown that uncircumcised men are more likely to infect and be infected by HIV. Recent
work suggests that the dendritic cells in the foreskin contain a molecule that may potentiate transmission, but more
needs to be done to pinpoint the exact mechanism. Several countries in sub-Saharan Africa have embarked on
programs to circumcise adult men. Surveys published in August of 2008 have found that men in Swaziland (which
has the highest rate of HIV-infection in the world today) wrongly think that circumcision is a complete protection
against infection with HIV.
Research18 indicates that injection of cocaine blunts the immune response to HIV, thus increasing the likelihood
of transmission and disease progression for addicts of the substance.
There are reports of HIV transmission by biting. The latest occurred in 1998; a 93-year-old man was robbed by
a female sex worker who was HIV+. After being serviced, the man refused to pay, they fought, and he bloodied her
15
SE Lipshultz and others. Cardiovascular status of infants and children of women infected with HIV-1 (Pediatric Pulmonary and
Cardiovascular Complications of Vertically Transmitted HIV Infection, P²C²HIV, study group): a cohort study.” Lancet. 2002;
360; 9330.
16
Although in Africa, some men much prefer having intercourse with a woman who has used herbs or astringents to dry the
vaginal mucosa. Such contact is extremely traumatic and most certainly causes a great deal of ripping and tearing, thus markedly
enhancing transmission.
17
Humphreys, et al., J Immunol 2002; 169:6316–6323. The presence of CCR5 receptors in macrophages was increased by 16- to
36-fold. Also CXCR4 receptors on macrophages were increased from 7- to 10-fold. Infiltrating T cells showed a 2.1-2.6-fold
increase of CCR5 receptors.
18
J Clin Endocrinol Metab 2003;88:00-00
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mouth, whereupon she bit him on the head, arm, and leg so severely that stitches were required. A test immediately
after the event showed the victim to be HIV-, but a test months later returned a positive result. After investigating
his personal life, authorities ruled out previous infection. (But one wonders! A 93-year-old frequenting a sex
worker?)
Free virus in the blood stream can last at most 6 hours; it needs to enter a cell to survive. Strangely enough, HIV
can remain viable in a refrigerated cadaver for several days, thus posing a danger to the pathologist who might
perform an autopsy on the body. The virus can also survive in a discarded syringe for more than a week if the
weather is not too warm.
Most HIV virions infect cells in the lymph nodes. Free HIV densities are highest in the cerebrospinal fluid,
lower in blood, much lower in sperm, and lowest in saliva and urine, and unmeasurable in perspiration.
Transmission via the urine and perspiration is not known to have occurred.
The only CDC-reported case of transmission via oral fluids (without biting) had several confounding factors. It
passed from an HIV+ male to his HIV- female partner. He had oral hairy leukoplakia (cancer of the mouth with
fissures on the tongue) and she had recently undergone oral surgery for gingivitis, so that there were recently
stitched incisions in her mouth and there was likely some exchange of blood. They claimed to have always practiced
safer sex, but there is some question about this. The CDC lists the probability of this transmission having occurred
orally at slightly less than 50%.
Coinfection with HIV and malaria increases the likelihood of vertical transmission. This is a common
occurrence that compounds the problem in central Africa.
It is known that vitamin A supplementation was associated with a 33% increased risk of transmission. For
women with low total lymphocyte counts, multivitamin use, without vitamin A, was associated with 63% lower
transmission rate and a 70% increase in two year survival rate for infants.
Transmission to health care workers via an accidental needlestick is unlikely. While the CDC reported such
events (which they no longer do), there were only a total of 58 such infections, with the highest number occurring
among lab technicians working with blood.
Opportunistic Infections
The two most common opportunistic infections are Pneumocystis jirovecii pneumonia (PJP19) and Kaposi’s
sarcoma (KS is initiated by Human Herpes Virus 8). PJP is a form of fungal pneumonia that causes the interstitial
regions of the lungs to fill with fluid. KS is a vascular malignancy that usually is first seen on the skin or mucous
membranes. It has been shown fairly convincingly that KS is most likely caused by human herpes virus 8 (HHV-8).
Prior to the appearance of AIDS, KS was a rather benign disease afflicting predominantly elderly men of
Mediterranean origin or Ashkenazi Jews. It was more a cosmetic problem than a medical one, since it affected only
the lower legs. People rarely died from it. Among AIDS patients, it can spread over the entire surface of the body
and even affect internal organs (so-called disseminated KS). The pictures below show mild KS lesions on the lower
legs and more severe lesions on the arm at the elbow.
Kaposi's sarcoma: left shows the characteristic "purple" lesions on the legs, while the person to the right
has a more extended case along the tricep and down the elbow.
19
This is a relatively recent renaming of Pneumocystis carinii pneumonia (PCP).
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15
AIDS is defined by the CDC to be a CD4+ count below 200, or CD4+ cells fewer than 14% of the lymphocytes.
This is usually followed by any of the listed recurring opportunistic infections for a person who is HIV+.
Remember, if a person’s CD4+ count rises above 200, they remain classified as a person-living-with-AIDS (PLWA)
for epidemiological purposes.
The opportunistic infections that characterize AIDS are classified and listed below.
Opportunistic Infections and Other HIV Complications
Bacterial and Mycobacterial Infections
• Mycobacterium avium complex (MAC)
• Salmonellosis
• Syphilis and/or neurosyphilis
• Tuberculosis
• Bacillary angiomatosis
Fungal Infections
• Aspergillosis
• Candidiasis
• Coccidioidomycosis
• Cryptococcal meningitis
• Histoplasmosis
Viral Infections
• Cytomegalovirus
• Hepatitis
• Herpes simplex
• Herpes zoster
• Human papillomavirus
• Molluscum contagiosum
• Oral hairy leukoplakia
• Progressive multifocal leukoencephalopathy
Neurologic Conditions
• AIDS dementia complex
• Peripheral neuropathy
Malignancies
• Kaposi’s sarcoma
• Non-Hodgkin’s lymphoma
• Primary central nervous system lymphoma
• Invasive cervical cancer
Protozoal or Fungal Infections
• Crytosporidiosis
• Isosporiasis
• Microsporidiosis
• Pneumocystis jirovecii pneumonia
• Toxoplasmosis
Other Conditions and Complications
• Aphthous ulcers
• Malabsorption
• Depression
• Diarrhea
• Thrombocytopenia
• Wasting syndrome
• Idiopathic thrombocytopenia purpura
• Listerosis
• Pelvic inflammatory disease
• Burkitt’s lymphoma
• Immunoblastic lymphoma
There is a rough relationship between CD4+ count and the appearance of certain opportunistic infections (the
emphasis here is on rough) as shown on the next page.
CD4+ Count
> 600, below normal
400–600
100–400
< 100
Opportunistic Infection
Tuberculosis, Herpes simplex, Herpes zoster, vaginal
candidiasis, oral hairy leukoplakia, Kaposi’s sarcoma
Bacterial infections: toxoplasmosis, cryptococcosis,
histoplasmosis, cryptosporidiosis
Pneumocystis jirovecii pneumonia, brain lymphoma
Cytomegaloviral infections
Studies have also shown that HIV-disease (or possibly the antiretroviral drugs used to treat it) is associated with
avascular necrosis (death of bone tissue), usually manifested as hip problems.
Some recent work attributes the decline from HIV-disease to AIDS as resulting from “oxidative stress.” The
idea is not accepted by the majority of medical researchers. Nevertheless, there is a great deal of evidence that
concomitant infection with human herpes virus-6 (HHV-6) is necessary for the development of AIDS.
As if all of this weren’t bad enough, AIDS patients have significantly increased risk of non- AIDS-related
cancers. Relative risk ratios (how much more likely one is of getting that cancer) ranged from a low of 1.8 for
stomach cancer to a high of 20.9 for skin cancer among men. For AIDS-related cancers, the relative risk ratio is 97.5
for men and 202.7 for women getting KS, 37.4 for men and 54.6 for women getting non-Hodgkin’s lymphoma, and
9.1 for women getting invasive cervical cancer. By the same token, AIDS-defining events cause an increase in the
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probability of death. Cytomegaloviral infections, esophageal candidiasis, Kaposi’s sarcoma, and bacterial
pneumonia increase that probability by a factor of from one to four, whereas mycobacterial infections,
toxoplasmosis, cryptococcosis, and progressive multifocal leukoencephalopathy increase it by a factor of from five
to ten. Non-Hodgkin’s lymphoma increase the rate by a factor of 19.
As seems to be the norm with HIV-disease and AIDS, there is also a totally counterintuitive finding: women
with AIDS have a reduced risk of developing either breast cancer or uterine cancer.
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Appendix
For diagnostic and record-keeping purposes, the WHO and CDC classify HIV/AIDS as follows:
WHO Staging System for HIV Infection and Disease in Adults and Adolescents (a)
Clinical stage I
Asymptomatic
Persistent generalized lymphadenopathy
Performance scale 1: asymptomatic, normal activity
Clinical stage II
Weight loss, <10% of body weight
Minor mucocutaneous manifestations (seborrheic dermatitis, prurigo, fungal nail infections, recurrent oral ulcerations,
angular cheilitis)
Herpes zoster within the last 5 years
Recurrent upper respiratory tract infections (ie, bacterial sinusitis)
And/or performance scale 2: symptomatic, normal activity
Clinical stage III
Weight loss, >10% of body weight
Unexplained chronic diarrhoea, >1 month
Unexplained prolonged fever (intermittent or constant), >1 month
Oral candidiasis (thrush)
Oral hairy leukoplakia
Pulmonary tuberculosis within the past year
Severe bacterial infections (ie, pneumonia, pyomyositis)
And/or performance scale 3: bedridden <50% of the day during the last month
Clinical stage IV
HIV wasting syndrome, as defined by the U.S. Centers for Disease Control and Prevention (CDC)*
Pneumocystis jiroveci (formerly carinii) pneumonia
Toxoplasmosis of the brain
Cryptosporidiosis with diarrhea >1 month
Cryptococcosis, extrapulmonary
Cytomegalovirus disease of an organ other than liver, spleen, or lymph nodes
Herpes simplex virus infection, mucocutaneous >1 month, or visceral any duration
Progressive multifocal leukoencephalopathy
Any disseminated endemic mycosis (ie, histoplasmosis, coccidioidomycosis)
Candidiasis of the esophagus, trachea, bronchi, or lungs
Atypical mycobacteriosis, disseminated
Nontyphoid Salmonella septicemia
Extrapulmonary tuberculosis
Lymphoma
Kaposi sarcoma
HIV encephalopathy, as defined by the CDC#
And/or performance scale 4: bedridden >50% of the day during the last month
(a) Proposed 'World Health Organization staging system for HIV infection and disease': preliminary testing by an international
collaborative cross-sectional study. The WHO International Collaborating Group for the Study of the WHO Staging System.
AIDS 1993 May;7(5):711-8.
Note: both definitive and presumptive diagnoses are acceptable.
*
HIV wasting syndrome: weight loss of >10% of body weight, plus either unexplained chronic diarrhea (>1 month) or chronic
weakness and unexplained prolonged fever (>1 month).
#
HIV encephalopathy: clinical findings of disabling cognitive and/or motor dysfunction interfering with activities of daily living,
progressing over weeks to months, in the absence of a concurrent illness or condition other than HIV infection which could
explain the findings.
CDC Categorization of HIV/AIDS (a)
The 3 CD4 count categories*
Category 1
>=500 cells/µL or more
Category 2
200-499 cells/µL
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Category 3
<200 cells/µL
*
Categorization should be based on the lowest accurate CD4 count, not necessarily the most recent one. So someone whose CD4
count declined steadily over a period of months until it reached 180 cells/µL, but then rose above 200 cells/µL again and
remained at that level (perhaps as the result of antiretroviral treatment), would be placed in category 3, not category 2.
The 3 clinical categories
Category A
One or more of the conditions listed below in an adolescent or adult (aged 13 years or older) with
documented HIV infection. Conditions listed in categories B and C must not have occurred.
asymptomatic HIV infection
persistent generalized lymphadenopathy (PGL)
acute (primary) HIV infection with accompanying illness (sometimes known as
seroconversion illness) or history of acute HIV infection
Category B*
Consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included
among conditions listed in category C and that meet one of the following criteria:
the conditions are attributed to HIV infection or are indicative of a defect in cell-mediated
immunity, or
the conditions are considered by physicians to have a clinical course or to require
management that is complicated by HIV infection
(This category includes all such symptomatic conditions, with the exception of those placed in
category C. Examples of conditions in this category include, but are not limited to: bacillary
angiomatosis, candidiasis (thrush) in the mouth and/or upper throat, candidiasis of the vagina
and/or vulva which is persistent, frequent, or responds poorly to treatment, cervical abnormalites
of moderate or severe extent or cervical cancer, constitutional symptoms such as fever (38.5°C) or
diarrhea lasting longer than 1 month, herpes zoster (shingles) involving at least 2 distinct episodes
or more than 1 dermatone (skin area), idiopathic thrombocytopenia purpura, listeriosis, oral hairy
leukoplakia, pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess,
peripheral neuropathy
Category C#
Includes the following conditions listed in the AIDS surveillance case definition.
ndida in the esophagus, trachea, bronchi, or lungs
invasive cervical cancer
coccidioidomycosis
Cryptococcus outside the lungs
cryptosporidiosis with diarrhea lasting for >1 month
CMV disease outside the liver, spleen, or lymph nodes
CMV retinitis
herpes simplex virus causing prolonged skin problems or involving the lungs or esophagus
HIV-related encephalopathy
chronic intestinal isosporiasis lasting >1 month
Kaposi sarcoma
Burkitt, immunoblastic, or primary (ie, not involving other parts of the body) brain
lymphoma
Widespread Mycobacterium avium intracellulare (MAI), M kansasii, or other species
Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)
recurrent bacterial pneumonia
progressive multifocal leukoencephalopathy (PML)
recurrent Salmonella septicemia
toxoplasmosis of the brain
HIV wasting syndrome
(a) Centers for Disease Control. 1993 Revised classification system for HIV infection and expanded surveillance case definition
for AIDS among adolescents and adults. MMWR Morb Mort Wkly Rep 1992; 41(RR-17):1-19.
*
For classification purposes, category B conditions take precedence over those in category A. For example, a patient previously
treated for oral or persistent vaginal candidiasis (and who has not developed a category C disease) but who is now asymptomatic
should be classified in clinical category B.
#
For classification purposes, once a category C condition has occurred, the person will remain in category C.
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