Human Immunodeficiency Virus and HIV Disease, October 2001

Retroviruses

Genetics of HIV

Types of HIV-1

Natural History of HIV Infection

How HIV Infects a Cell

Transmission Rates for HIV

Opportunistic Infections

Objectives

 

Students need to know the terms in blue.

 

Retroviruses

HIV is an abbreviation for Human Immunodeficiency Virus. There are two main forms of HIV: 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 Cameroon in 1985. HIV-2 is more similar to SIV (Simian Immunodeficiency Virus) than is HIV-1 and it is much less virulent (usually not resulting in full blown AIDS, but still fatal). [It is also rarer 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.]. 

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) STD clinic in Kinshasa and analyzed in 1998 to establish this record. There is even one case dating back to 1934 that is suspected, but not verified for lack of tissue and/or blood samples.

On February 1, 2000, Bette Korber, et al. reported the results of a phylogenetic statistical analysis of the evolution of the retroviral genome of HIV using complex mathematical models allowing for both constant and variable rates of evolution. Her group's analysis required the use of parallel supercomputers to backtrack the evolution to its source from monkeys (the chimpanzee species, Pan troglodytes troglodytes to be exact.). The computed model correctly placed the genome of the 1959 case on an evolutionary tree. The model estimates based on the latest data set the most reliable time of origin of the disease in humans as somewhere around 1931±15. As the number of (captive) chimps analyzed has increased the width of the confidence interval has decreased. In the January 18, 2002 issue of Science, Hahn and Shaw reported the first chimp in the wild detected to have an SIV infection. The analysis was based on fecal samples. Anne-Mieke Vandamme of the Rega Institute in Belgium headed a group dating the virus using other techniques and concluded that a transfer from animals to humans occurred around 1675 with a confidence interval of between 1590 and 1760.

HIV-2 has been traced to the Simian Immune Virus (SIV) carried by sooty mangabeys. In fact, the genetic sequence of the two viruses are more alike than those of HIV-1 and HIV-2. During the 8^th Annual Retrovirus Conference in February 2001 Beatrice Hahn and Eric Delaporte reported on cross species infections. They have 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. This result seems to indicate the possibility of further animal to human transmission!

Several naysayers have claimed that HIV-disease originated or was extended by the purported use of African green monkey kidneys to cultivate Kaprowsky's CHAT polio virus vaccine in the late 1950s and early 1960s. The author Edward Hooper raised these issues in his book The River published in 1999. A review of the book is available on the Poz website at link. Both Korber's and Vandamme's analyses find that argument of origin to be a very low probability event, hence quite unlikely. Samples held at the Wistar Institute have been analyzed and no trace of HIV or SIV was present. Whether or not HIV was extended by the immunization program remains to be conclusively decided. A meeting to settle this issue was sponsored by the British Royal Society and is reported in a Medscape article written by Jonathan Weber available at link.  A more recent article by *** suggests that the near universal use of injection drugs and reusing nonsterile syringes beginning in the 1950s likely enhanced the spread of many infectious diseases.

 

HIV is a special type of retrovirus containing RNA. Not all RNA viruses are retroviruses, e.g., the measles virus and flu virus are RNA viruses, but not retroviruses. There are three families of retroviruses: oncoviruses (causing cancer), lentiviruses (slow viruses, of which HIV is one), and foamy viruses or spumaviruses (about which much less is known). There are also retroviral infections of animals, e.g., SIV (simian immunodeficiency virus) infects nonhuman primates, FIV (feline immunodeficiency virus) affects cats, and visna virus infects sheep.

The distinguishing feature of all retroviruses is that they replicate backward;

RNA® ssDNA (single strand DNA)® dsDNA (double strand DNA)® RNA® protein synthesis

using the enzyme reverse transcriptase in the first two steps. The first two steps of this process have no error-correction mechanisms.

The three enzymes found inside a retrovirion are reverse transcriptase, integrase, and protease.

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Genetics of HIV

HIV contains nine genes made of 9749 base pairs. [SIV has ten genes.] 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 (codes for the surface proteins gp120 and gp41 that protrude from the lipid envelope and attach to cellular receptors using about 1800 bp). Other genes within HIV are tat (transactivator protein), rev (regulator of expression of virus protein), vif (virus infectivity factor), nef (misnamed negative regulator factor, but really an enhancing factor), vpr (virus protein R), and vpu (virus protein U).

The term gp# stands for glycoprotein of molecular weight # kiloDaltons. p# is a protein of molecular weight # kiloDaltons. The gp120 connected to the gp41 stem is collectively called gp160 and it is this protein, together with other coreceptors, that must connect to the CD4 receptor of T cells. There are about 75 gp160 spikes on each virion. p24 is found both on and within the capsid.

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Types of HIV-1

Cells that use DNA to replicate are relatively stable and do not mutate readily because the double strand DNA carries its own error-correcting mechanisms. But, retroviruses go backward 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 mechanism for error-correction. It is claimed that reverse transcriptase, which governs this reaction, introduces a mutation an average of once in every 5000–10,000 nucleotides; that's one or two 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. Most such mutations affect the env gene, producing different envelope glycoproteins within a given individual. Some HIV strains cannot infect certain CD4+ cell lines. Some variants can enter T cells but not macrophages and vice-versa.

The HIV variants are divided into three groups: M, for major, N, and O, for other or outlier. Within the M-group 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, Europe, Southeast Asia, and South America. Clades E and C are dominant in Asia and A, C, and D are dominant in Africa. Each of the five clades differs from each other by as much as 35%.

In the September 1, 1998 issue of Nature Medicine, F. Simon announced the discovery of a 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. It is the N-group. 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.

Group O contains about thirty subtypes found mainly in West African countries such as Cameroon, Gabon, etc. It has higher prevalence than the N-group, but much lower than the M-group. [This nomenclature is in the process of being revised.]

A summary of the geographical distribution of the M-group HIV-1 subtypes is given below.

 

The Sixth Meeting on Retroviruses and Opportunistic Infections held in Chicago from January 31, 1999 to February 4, 1999 carried 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 spread. The 8^th Conference in 2001 saw the publication of research indicating that as many as 14% of new infections are recombinant. Some researchers claim that the recombinant strains are not as hardy as the so-called wild strains. Perhaps that is wishful thinking, but that remains to be seen.

The distribution of cases in the US in 1997, broken down by census group is somewhat troubling:

 

Clearly, people of color are inordinately affected by this disease.

About 10% of HIV infected people progress to AIDS within 2 or 3 years of infection (rapid progressors). About 60% of 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. The Centers for Disease Control and Prevention provide the following graphs of the number of virions per milliliter as a function of time for each of the three groups.

 

For more about these graphs, see the next section.

A result published in the August 1999 issue of the Journal of Infectious Diseases 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. The virus then enters a middle phase where it is dual tropic and its envelope protein gp120 can bind to the chemokine 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. Since HIV can attach to the CXCR4 receptor that is present on CD8+ cells, it can also attack T cytotoxic cells. Work announced in 11/2000 indicates 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. A report by Burton et al. in the January 2001 issue of the Journal of Immunology 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."

The January 2001 online version of the Proceedings of the National Academy of Sciences carried a report from NIAID scientists suggesting that macrophages can continue to produce new virions even after CD4+ cells have been depleted. This makes macrophages another reservoir for the virus.

Some people, mostly of north European ancestry, have mutations in the genes that code for CCR5. When the mutation, called D32 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 immune to infection by this form of HIV! Another mutation that changes the form of CXCR4 has been shown to lead to a condition similar to long-term nonprogression. This mutation is also found almost exclusively among people of northern European ancestry. Only 1% of the whites of European ancestry are D32-homozygous and it appears to be entirely absent in Japan and Central America. About 20% of whites of European ancestry are D32-heterozygous. 

One theory held that this genetic deletion had occurred about 700 years ago, making the global Plague pandemic as a possible candidate as the cause. Further research showed that infection by Yersinia pestis does not use chemokine receptors, thus debunking this theory. Recent work published in the December 3, 1999 issue of Science 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 holds that ancestors of survivors of an ancient smallpox outbreak seem to have inherited a resistance to HIV infection! Unfortunately, with good news comes bad news. On February 7, 2001 Woitas, et al. announced the results of a study of people with this homozygous deletion who were also infected with hepatitis C. Patients who were coinfected had much higher levels of 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 D32-deletion. This seems to indicate that this genetic mutation leads to an increased risk for HCV infection and a worse outcome, to boot.

On the plus side, people coinfected with the hepatitis-5 virus (GBV-C) seem to show an improved survival rate.

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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 (1–2 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 = mL = 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.

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 which follows, there are few, if any, symptoms. The T4 cell count may return to the normal range of 800–1200/mL, 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 fall.

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 listerosis.

As the T4 cell count continues to fall below 200, other opportunistic infections (Pneumocystis carinii pneumonia, Kaposi's sarcoma, candidiasis, coccidioidomycosis, cryptosporidiosis, cytomegaloviral infections, toxoplasmosis of the brain, HIV encephalopathy, etc.) ravage the body until one or more 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 cancers, and the remainder die of other causes.

The CDC defines the onset of AIDS for an HIV+ person as that time when the CD4 T cell count falls below 200 or 14% of lymphocytes and there are concomitant infections listed at the end of this article. Since this is strictly for epidemiological purposes, once as person is classified as an AIDS patient, they are always classified as an AIDS patient, no matter how high their CD4+ count may go after taking medications.

A great deal of recent research (1/99 and 2/99) 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. A paper (7/99) found evidence of accelerated 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.

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. 

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, only 2% of the virus are in the circulating blood and the rest 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.

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.

Another graph of viral load and CD4+ counts as a function of time shows the progression of the disease.

You should notice that the viral load is highest during the acute stage of infection. 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+ dashed curve at the maximum of the viral load is where the body mounts an HIV-specific 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.

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How HIV Infects a Cell

HIV follows these steps as it infects cells and reproduces. (1) Attachment of the virion to the receptor on the cell. In the case of HIV, its gp120 attaches to a T4 cell's, or macrophage's, CD4 receptor and the coreceptor CCR5 and/or CXCR4 = fusin. The following picture shows (artificially colored purple) virions on the surface of a (salmon colored) T cell.

 

(2) Fusion with the cell membrane. The following diagram illustrates this process. The receptors from the virions lock to those of the cell. Then the virus receptors pull back and force a contact with the cell membrane. The rest is history.

(3) Penetration of the cell membrane, (4) Uncoating, whereby the virion sheds its coat and leaves the 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 to the nucleus of the cell. (8) Integration into the host nucleus using the enzyme integrase. The integrated DNA form of the virus is called a provirus. (9) Viral transcription. Once within the host cell's nucleus, HIV transfers its genetic code to that of the host and henceforth, the host cell can become a virus factory. The cell could lie dormant (non-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. (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. 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.

The virus lodges in the follicular dendritic cells of the lymph system. In addition, the virus can hitch a ride on the dendritic-like cells present in the mucosa (in particular, the anal, vaginal, and oral mucosa), using a receptor designated DC-SIGN, without infecting the cell (van Kooyk, Figdor, et al. March 3, 2000 Cell). These cells also migrate to the lymph nodes. Once there, the virus attacks the T4 cells. After an extended period of fighting the virus, the body succumbs and the dendritic cells in the lymph nodes 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.

 

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 T8 cells, the lower the reproduction rate of the virus. On the other hand, Saha, et al. published an article in the January 2001 issue of Nature Medicine showing that HIV can infect CD8+ cells without using either CD4 as a primary receptor nor either of the coreceptors CCR5 or CXCR4.

Research announced at the Twelfth International AIDS Conference in Geneva, Switzerland (6/98) showed that HIV can remain in resting (non-reproducing) T cells in so-called "latent reservoirs," even after intensive drug therapy. Later work (5/99) estimated that the half-life of these latent reservoirs may be as long as forty to sixty years! Martin, et al. from NIH reported in January of 2001 that macrophages may also be latent reservoirs for HIV!

HIV 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.

 

Since macrophages have some CD4 receptors, they too are targets for HIV infection. Once infected, their lifespans 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 infected. 

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 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.

In the December 15, 2000 issue of the Journal of Immunology, Marone and his colleagues at the University of Naples in Italy have 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.

HIV 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. At the December 1998 meeting of the American Society for Cell Biology, Soll, et al. reported that syncytia are much more common than previously thought. His 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.

The journal AIDS 15:1627-1634 carried an article by P. Corbeau, et al. showing that as the CCR5 density on CD4+ cells increases so too does disease progression. Other work has shown that HIV can 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. [Cole, et al. Proceedings of the National Academy of Sciences] [The sample size was only 7.]

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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 are 

1. transfusion of infected blood or non-artificial infected blood products, 
2. needle sharing among infected injection drug users, 
3. sexual transmission involving the exchange of blood, semen, seminal fluid, or vaginal fluids
4. needlesticks and open cuts exposed to infected fluids, 
5. piercing the skin with contaminated instruments in ear-piercing, tattooing, and acupuncture, 
6. injection with contaminated unsterilized syringes. 
7. vertical transmission can occur during birth and as a result of breast-feeding. 

Since its discovery in 1983, no new modes of transmission of HIV have been discovered. HIV cannot be transmitted by touch, by insect vectors, or across fomites. Currently, blood supplies are screened for hepatitis, HIV, and other infections. Consequently, the odds of infection in a randomly selected blood transfusion are about one in 400,000.

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. Transfusion of tainted blood has an 80–90+% rate of transmission, whereas 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 either or both persons due to other sexually transmitted diseases (STDs). 

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.

In 1992 Naftalin authored an article in the journal Nature showing that human sperm contains collegenase and spermine which cause a breakdown of the membrane that supports the colonic epithelium of the rectal mucosa. This causes a significant decrease in the mucosal immunity and allows pathogens to more easily penetrate these tissues. Current knowledge is that unprotected anal intercourse is the most efficient method of sexual transmission. 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 to date for oral-genital transmission are about 1 in 4500. But the large number of such contacts among men having sex with men (MSM) leads to rather larger incidence rates than this low transmission rate number would otherwise indicate.

There are reports of HIV transmission by biting. The latest occurred in 1998; a 93-year-old man was robbed by a prostitute who was HIV+. After being serviced, the man refused payment, 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!)

Free virus in the blood stream can only last about 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.

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 case of transmission via oral fluids 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%.

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 of vitamin A), 
8. the presence of STDs, and 
9. the lack of medical treatment for HIV-disease. 

Recent (6/2001) estimates of the transmission rates indicate that fully 80% of the rate can be attributed to the birthing process and the remaining 20% is due to blood exchange during gestation. Once delivered, the child must face the risk associated with breast-feeding, which alone accounts for 10–20% of the worldwide transmissions to newborns. Several studies have shown that varying types of therapy using AZT and/or nevirapine can greatly reduce the transmission rate from a high of 25–30% 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 them.

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Opportunistic Infections

The two most common opportunistic infections are Pneumocystis carinii pneumonia (PCP) and Kaposi's sarcoma (KS). PCP 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. Works published in March, April, June, and December of 1998 have 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. Among AIDS patients, it can spread over the entire surface of the body and even affect internal organs. The picture below shows KS lesions on the arm at the elbow.

 

AIDS is defined by the CDC to be a CD4+ count below 200, CD4+ cells fewer than 14% of the lymphocytes, and/or any of the listed recurring opportunistic infections for a person who is HIV+. If  a person's CD4+ count rises above 200, they remain classified as a person-living-with-AIDS for epidemiological purposes.

The opportunistic infections that characterize AIDS are classified and listed below.

 

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).

Some recent work attributes the decline from HIV-disease to AIDS as resulting from "oxidative stress." Unfortunately, the term is neither well-defined nor accepted by the majority of medical researchers.

As if all of this weren't bad enough, AIDS patients have significantly increased risk of non-AIDS-related cancers. Brian Gallagher, et al. published this work in the American Journal of Epidemiology of 9/15/2001. 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.

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Objectives

Know: difference between HIV-1 and HIV-2, retrovirus, lentivirus, reverse transcriptase, integrase, protease, number of genes in HIV, gp41, gp120, gp160 spikes, p17, p24; M, N, and O subtypes, clades of HIV, which are dominant where, wild and recombinant strains; rapid progressors, slow progressors, and nonprogressors, and the relationship with primary HIV infection (PHI); M-tropic, dual tropic, and T-tropic forms, and alternate binding sites for each: CCR5 and CXCR4; heterozygous and homozygous mutation, delta-32 deletion and its possible relation to infection and speed of progression; natural history of HIV infection, acute stage, window period and seroconversion, set point, constitutional symptoms, viremia and viral load; be able to draw curves of viral load and CD4+ counts versus time for an infected person; steps by which HIV infects a T cell; apoptosis or programmed cell death; AIDS dementia and why it can happen, syncytia formation; modes of transmission and corresponding rates of transmission; major opportunistic infections, especially PCP, MAC, CMV, and KS.

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