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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. ©PGB 1 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. ©PGB 2 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. ©PGB 3 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. ©PGB 4 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. ©PGB 5 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. ©PGB 6 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. ©PGB 7 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. ©PGB 8 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. ©PGB 9 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. ©PGB 10 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. ©PGB 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 shaking hands, dry kissing, sharing eating utensils, insect vectors, hugging, 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 ©PGB 12 tears, sputum, saliva, feces, urine, or emesis (vomit). 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. ©PGB 13 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 ©PGB 14 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). ©PGB 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 ©PGB 16 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. ©PGB 17 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 ©PGB 18 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. ©PGB 19