ACQUIRED IMMUNO DEFICIENCY SYNDROME ( AIDS )
The primary infection in AIDS ranges from asymptomatic to an infectious mononucleosis-like illness with up to a few weeks of fever, malaise, arthralgias, and rash. A long (years) asymptomatic period follows, after which the disease, AIDS, emerges. The progressive findings directly due to the virus are wasting, diarrhea, neurologic degeneration, and malignancies. The effect of the virus on the immune system causes an extensive array of viral, bacterial, fungal, and parasitic opportunistic infections whose findings are the same or worse than those seen in patients without AIDS.
The AIDS syndrome was first recognized in the United States in 1981, when it became apparent that an unusual number of rare skin cancers (Kaposi’s sarcoma) and opportunis-tic infections were occurring among male homosexuals. These patients were found to have a marked reduction in CD4 T lymphocytes and were subject to a wide range of opportunistic infections normally controlled by an intact immune system. The disease was found to progress relentlessly to a fatal outcome and was first identified in male ho-mosexuals, hemophiliacs who were receiving blood-derived coagulation factors, and in-jection drug users.
Retrospective serologic studies with material saved from patients in various studies indicate that the disease was already occurring in Africa in the 1950s and in the United States in the 1970s. In 1985, HIV-2 was found to be endemic in parts of West Africa and to cause AIDS. To date, this virus has been relatively restricted geographically, although HIV-2 infections have occurred in the western hemisphere.
The HIV virus is transmitted between humans in three ways: sexually, perinatally, and by exposure to contaminated blood or body fluids. The virus has been demonstrated in par-ticularly high titers in semen and cervical secretions, and the majority of cases result from sexual contact. Infection is facilitated by breaks in epithelial surfaces, which provide di-rect access to the underlying tissues or bloodstream. The relative fragility of the rectal mucosa, together with large numbers of sexual contacts, are probable contributing factors to the predominance of the disease among promiscuous male homosexuals. Transmission appears to be more efficient from men to women, but the reverse is clearly documented. The probability of HIV transmission per unprotected sexual act is estimated at 0.0003 to 0.0015. The risk of perinatal transmission from an infected mother to her child has been estimated to range from 15 to 40%.
Growth of the virus in cell culture and identification of its antigens allowed develop-ment of effective test procedures for detecting HIV infection. These almost eliminated the risk of transmission by blood transfusion; testing of donors and the use of recombinant or specially treated coagulation factors have now virtually eliminated these sources of infec-tion. Until serologic tests for the infection became available, in 1985, more than 10,000 cases of AIDS were probably acquired in the United States through blood transfusion, and about 80% of hemophiliacs treated with coagulation factors derived from pooled blood sources became infected. Transmission of infection by blood is now largely associ-ated with sharing of needles and syringes by injecting drug users, and this has been an in-creasing source of the disease. In some areas of the world, the seroprevalence of HIV positivity among injecting drug users has been as high as 70%. It became apparent that heterosexual transmission could occur and that the infection could be transmitted from mother to infant either by intrauterine spread or during the birth process. It was also found that the disease had its greatest prevalence in parts of Africa, where the spread was pre-dominantly heterosexual.
Transmission of infection to health care workers after accidental sticks with potentially contaminated needles is very rare (considerably less than 1% of occurrences), presumably because the amount of infectious virus in the blood of infected cases is small and larger volumes or repeated exposures are needed for a significant chance of infection. Neverthe-less, cases have occurred from both clinical and laboratory exposure, and extreme care in handling needles, sharps, and so on, is necessary. Transmission does not occur through day-to-day nonsexual contact with infected individuals or through insect vectors, because of the fragility of the virus and the need for direct mucosal or blood contact. It is of interest that the virus has been detected in saliva, tears, urine, and breast milk. With the possible exception of breast milk, these sources have not been shown to be infectious.
As of December 2001, there have been 816,000 cases of AIDS in the United States, with 468,000 deaths. The highest prevalence rates of HIV infections have been in homosexual and bisexual males, intravenous drug users, prostitutes, and sexual partners of HIV-infected per-sons. In some areas of the United States, 40 to 60% of homosexual males attending sexually transmitted disease clinics were found to be infected. The epidemiology of HIV infection is changing in the United States as the pandemic evolves and as the modes of transmission be-come more generally understood. The numbers and proportions of heterosexually transmit-ted, drug abuse – related, and neonatal cases are increasing, particularly among the poor and disadvantaged racial minorities. Antibody rates in prostitutes may be as high as 40%, de-pending partly on the degree of associated intravenous drug abuse. Prevalence rates in the heterosexual population, in general, are currently less than 1% but have been increasing. In 1985 in the United States, only 7% of AIDS cases were in women; by 2000 the percentage had risen to 25%. Approximately 2000 newborns per year are infected by HIV perinatally, but this number may be decreasing as more pregnant women receive antiretroviral therapy. The current distribution of AIDS cases is men who have sex with men (MSM) (40%), in-travenous drug users (30%), heterosexual (25%) persons, and others (5%). Black patients now account for 50% of cases, exceeding the percentages in non-Hispanic white men.
In contrast to the situation in the United States and Western Europe, heterosexual trans-mission is the primary route of transmission in Africa and Asia, where there is an approxi-mately equal distribution of infection and disease between the sexes. This may be due to a high frequency in these areas of ulcerative genital lesions caused by other sexually trans-mitted diseases. These lesions facilitate passage of virus into the tissues of others during intercourse. In central and eastern Europe, where there is an emerging epidemic, the most common risk factor is intravenous drug use.
AIDS has been reported in more than 150 countries. The disease continues to spread rapidly in Africa and South America. In sub-Saharan Africa alone, 25 million people are infected, and there are 4 million new cases per year. Until recently, the Far East had few cases, but now there is epidemic spread, especially in South and South East Asia (India, South China, Burma, Thailand, Cambodia, Viet Nam, and Malaysia). In China, there are more than 600,000 patients with AIDS, and the rate of new cases is increasing by more than 30% per year. HIV-2 infection is found primarily in West Africa and is spread by heterosexual transmission. Infection by this virus has, however, been reported in Europe in homosexual men, injection drug users, transfusion recipients, and hemophiliac men. For example, in Russia, there were 40,000 new cases of AIDS in 2000. In some countries in Africa, 25% of the population and up to 60% of women are HIV antibody – positive.
The pathogenesis of HIV-1 infection is very complex, but the following factors are likely to be important in the disease-causing process.
The initial target of HIV-1 is CD4 molecules, particularly on the surface of CD4 helper T + lymphocytes, monocytes, and macrophages. The virus can also infect other human cells expressing CD4, and a wide range of CD4 negative cells, including renal and gastrointesti-nal epithelium and brain astrocytes. The mechanism for infection of non – CD4-bearing cells is unknown but may involve other receptors or fusion with cells already infected with HIV. The virus replicates in macrophages, and these cells could serve as a reservoir for continued expansion of the infection to other cell types by cell-to-cell fusion, which allows the virus to spread without being exposed to neutralizing antibody. Infected macrophages may participate in breakdown of the blood – brain barrier, allowing enhanced exposure of the central nervous system (CNS). Although CNS and intestinal disturbances are a promi-nent part of fully developed AIDS, it is not clear whether they are a direct result of infec-tion of these cells or mediated by cytokines from infected macrophages and T lympho-cytes.
Kinetic studies of changes in viral load with antiviral therapy demonstrated the half-life of HIV in plasma is 5 to 6 hours. In other words, more than 50% of the viral load measured on any given day has been produced in the past 24 hours. Because 99% of the viral load is produced by cells that were infected within the past 48 to 72 hours, cell turnover must be equally rapid. Indeed, when similar kinetic studies are performed on changes in CD4 cell counts, it is estimated that up to 1 billion CD4 cells are produced per day in response to the infection and that the half-life of these cells is only 1.6 days.
The long asymptomatic period following HIV infection (clinical latency) occurs despite active virus replication in the host. Several factors can terminate the long latent period of HIV-1. Mutations occur during viral replication that appear to enhance induction of viru-lent forms of the virus, with increased cytopathic capacity and altered cell tropisms. Thus, the mutated forms of HIV-1 isolated from later stages of disease infect a broader range of cell types and grow more rapidly than those isolated in the asymptomatic period. Initially, it was believed that little or no viral replication occurred during this latent period, but studies of lymph nodes of individuals with early asymptomatic disease have shown in-tense immunologic reactions within the lymphoid tissue at early stages of disease. This implies that the immune system is capable of controlling the virus to some degree early in the course of disease, an ability that is later lost as the disease progresses over time.
Recent studies of HIV infection have shown that the level of free virus in the plasma increases in direct relation to the stage of disease. Individuals with early-stage disease have less than 10 infectious virions/mL of plasma, whereas those in late-stage disease have between 100 and 1000 infectious virions/mL of plasma. These studies imply either that viral replication was increasing during later stages of disease due to more virulent mutations and/or the immune system had lost its ability to clear free virus as the disease progresses.
The primary immune defect in AIDS results from the reduction in the numbers and effec-tiveness of CD4+ helper-inducer T lymphocytes, both in absolute numbers and relative to CD8+ suppressor T lymphocytes. This is due to direct killing of CD4+ T lympho-cytes by the virus but may also involve other mechanisms as well. These include sec-ondary killing of uninfected (bystander) cells during cell fusion, autoimmune processes that lead to the elimination of CD4+ T lymphocytes by opsonophagocytosis, and anti-body-dependent cell-mediated cytotoxicity (ADCC) directed at gp120 expressed on the CD4+ cell surface. There are also functional defects in CD4+ T lymphocytes affecting lymphokine production and leading to inhibition of some macrophage functions.
Effects on CD4+ T lymphocytes thus lead to a generalized failure of cell-mediated immune responses, but there is also an effect on antibody production due to polyclonal activation of B cells, possibly associated with other viral infections of these cells. This overwhelms the capacity of infected individuals to respond to specific antigens. The end result of these processes is a disturbance of immune balance that can give rise to malig-nancies as well as the susceptibility of AIDS patients to a range of opportunistic viral, fungal, and bacterial infections.