Reconstruction and future trends of the AIDS epidemic in the United States

There has been considerable uncertainty in estimates of past and current human immunodeficiency virus (HIV) infection rates in the United States. Statistical estimates of historical infection rates can be obtained from acquired immunodeficiency syndrome (AIDS) incidence data and the incubation period. However, this approach is subject to a number of sources of uncertainty and two other approaches, epidemic models of HIV transmission and surveys of HIV prevalence, are used to corroborate and refine the statistical estimates. Analyses suggest the HIV infection rate in the United States grew rapidly in the early 1980s, peaked in the mid-1980s, and subsequently declined markedly. Due both to the decline in the underlying infection rate and to the development of effective therapies that may delay AIDS diagnosis, overall AIDS incidence may plateau during the next 5 years. However, the number of individuals with advanced HIV disease without a diagnosis of AIDS who could potentially benefit from therapy is expected to increase 40% by 1995 as infected individuals progress to more advanced stages of HIV disease. Thus, although the overall HIV infection rate has declined, the demands on the U.S. health care system for treatment and care of HIV-infected individuals remain enormous.     

A larger spectrum of severe HIV-1--related disease in intravenous drug users in New York City

Increasing mortality in intravenous (IV) drug users not reported to surveillance as acquired immunodeficiency syndrome (AIDS) has occurred in New York City coincident with the AIDS epidemic. From 1981 to 1986, narcotics-related deaths increased on average 32% per year from 492 in 1981 to 1996 in 1986. This increase included deaths from AIDS increasing from 0 to 905 and deaths from other causes, many of which were infectious diseases, increasing from 492 to 1091. Investigations of these deaths suggest a causal association with human immunodeficiency virus (HIV) infection. These deaths may represent a spectrum of HIV-related disease that has not been identified through AIDS surveillance and has resulted in a large underestimation of the impact of AIDS on IV drug users and blacks and Hispanics.     

AIDS: an international perspective

The acquired immunodeficiency syndrome (AIDS) and infection with the human immunodeficiency virus type 1 (HIV-1) constitute a worldwide public health problem. Whereas in Europe and in most of the Americas transmission of HIV-1 has occurred predominantly among homosexual men and intravenous drug abusers, in Africa a distinct epidemiologic pattern has emerged that indicates that HIV-1 infection is mainly heterosexually acquired. Heterosexual transmission appears to be increasing in some parts of Latin America and the Caribbean, and possibly in the United States. In addition to HIV-1, at least one other human retrovirus, namely HIV-2, has been implicated as a cause of AIDS in Africa and Europe. Factors that influence heterosexual transmission of HIV-1 include genital ulcerations, early or late stages of HIV-1 infection in the index case, and possibly oral contraception and immune activation. The rate of perinatal transmission is enhanced when the mother's illness is more advanced. AIDS and HIV-1 infection may have a significant impact not only on public health, but also on the demography and socioeconomic conditions of some developing countries. Programs for the prevention and control of AIDS should be an immediate priority in all countries.     

Transmission of HIV in Belle Glade, Florida: lessons for other communities in the United States

The high cumulative incidence of AIDS and the large percentage of AIDS patients with no identified risks in Belle Glade, Florida, were evaluated through case interviews and neighborhood-based seroepidemiologic studies. It was found that of 93 AIDS patients reported between July 1982 and 1 August 1987, 34 could be directly linked to at least one other AIDS patient or to a person with AIDS-related complex by sexual contact, sharing of needles during intravenous drug abuse (or both), or perinatal exposure; of 877 randomly selected adults, 28 had antibodies to HIV; no person over age 60 and none of 138 children aged 2 to 10 years had antibodies to HIV; no clustering of infected persons within households occurred, except in sex partners; and HIV-seropositive adults were more likely than HIV-seronegative adults to be from Haiti, have a lower income, report sex with intravenous drug abusers, and have a history of previous treatment for sexually transmitted diseases. The presence of antibodies to five arboviruses prevalent in South Florida or the Caribbean did not correlate significantly with HIV infection. The high cumulative rate of AIDS in Belle Glade appears to be the result of HIV transmission through sexual contact and intravenous drug abuse; the evidence does not suggest transmission of HIV through insects.     

AIDS in Africa: an epidemiologic paradigm

Cases of the acquired immune deficiency syndrome (AIDS) have been reported in countries throughout the world. Initial surveillance studies in Central Africa suggest an annual incidence of AIDS of 550 to 1000 cases per million adults. The male to female ratio of cases is 1:1, with age- and sex-specific rates greater in females less than 30 years of age and greater in males over age 40. Clinically, AIDS in Africans is often characterized by a diarrhea-wasting syndrome, opportunistic infections, such as tuberculosis, cryptococcosis, and cryptosporidiosis, or disseminated Kaposi's sarcoma. From 1 to 18% of healthy blood donors and pregnant women and as many as 27 to 88% of female prostitutes have antibodies to human immunodeficiency virus (HIV). The present annual incidence of infection is approximately 0.75% among the general population of Central and East Africa. The disease is transmitted predominantly by heterosexual activity, parenteral exposure to blood transfusions and unsterilized needles, and perinatally from infected mothers to their newborns, and will continue to spread rapidly where economic and cultural factors favor these modes of transmission. Prevention and control of HIV infection through educational programs and blood bank screening should be an immediate public health priority for all African countries.     

A tale of two futures: HIV and antiretroviral therapy in San Francisco

The effect of antiretroviral therapy (ART) in preventing human immunodeficiency virus (HIV) infections and averting acquired immunodeficiency syndrome (AIDS) deaths in the San Francisco gay community over the next 10 years was predicted. A transmission model was coupled with a statistical approach that enabled inclusion of a high degree of uncertainty in the potential treatment effects of ART (in terms of infectivity and survival), increase in risky behavior, and rate of emergence of drug resistance. Increasing the usage of ART in San Francisco would decrease the AIDS death rate and could substantially reduce the incidence rate.     

The epidemiology of AIDS: current status and future prospects

The reported incidence of acquired immune deficiency syndrome (AIDS) continues to increase in countries throughout the world. On the basis of a polynomial model for extrapolation, the cumulative number of cases diagnosed and reported since 1981 in the United States is expected to double during the next year with over 12,000 additional cases projected to be diagnosed by July 1986. The annual incidence rates for single (never-married) men in Manhattan and San Francisco, intravenous drug users in New York City and New Jersey, and persons with hemophilia A ranged from 261 to 350 per 100,000 population during 1984. For single men aged 25 to 44 years in Manhattan and San Francisco, AIDS was the leading cause of premature mortality in 1984 as measured by years of potential life lost. Infection with HTLV-III/LAV is considerably more common than reported AIDS in high-risk populations and can persist at least for several years, so the presence of specific antibody should be considered presumptive evidence of current infection. The screening of donated blood and plasma for antibody to HTLV-III/LAV and use of safer clotting factor concentrates should greatly reduce HTLV-III/LAV transmission through blood and blood products. Most HTLV-III/LAV infections occur through sexual transmission, use of contaminated needles, and as a result of infected mothers passing the virus to newborns. Continued research commitment is needed to develop an HTLV-III/LAV vaccine and therapy for this infection. In the interim, widespread community efforts are needed to minimize transmission.     

A model-based estimate of the mean incubation period for AIDS in homosexual men

Because of the difficulty in identifying the date of exposure to type 1 of the human immunodeficiency virus (HIV-1) infection in persons other than transfusion recipients, studies of the incubation periods for acquired immunodeficiency syndrome (AIDS) have been limited. When data from a cohort of 84 homosexual and bisexual men that provided the information to determine the years of conversion of sera infected with HIV-1 were analyzed, a model for the proportion likely to develop AIDS and the incubation period for AIDS in homosexual men could be derived. The maximum likelihood estimate for the proportion of infected homosexual men developing AIDS is 0.99 (90% confidence interval ranging from 0.38 to 1). Furthermore, the maximum likelihood estimate for the mean incubation period for AIDS in homosexual men is 7.8 years (90% confidence interval ranging from 4.2 years to 15.0 years), which is close to the estimate of 8.2 years for adults developing transfusion-associated AIDS.     

A formalin-inactivated whole SIV vaccine confers protection in macaques

A vaccine against human immunodeficiency virus (HIV) would be highly effective in stopping the acquired immunodeficiency syndrome (AIDS) epidemic. A comprehensive evaluation of potential vaccine methodologies can be made by means of the simian model for AIDS, which takes advantage of the similarities in viral composition and disease potential between simian immunodeficiency virus (SIV) infection of rhesus macaques and HIV infection in humans. Immunization with a formalin-inactivated whole SIV vaccine potentiated with either alum and the Syntex adjuvant threonyl muramyl dipeptide (MDP) or MDP alone resulted in the protection of eight of nine rhesus monkeys challenged with ten animal-infectious doses of pathogenic virus. These results demonstrate that a whole virus vaccine is highly effective in inducing immune responses that can protect against lentivirus infection and AIDS-like disease.     

Natural SIV hosts: showing AIDS the door

Many species of African nonhuman primates are naturally infected with simian immunodeficiency viruses (SIVs) in the wild and in captivity. In contrast to HIV-infected humans, these natural SIV hosts typically do not develop AIDS, despite chronic infection with a highly replicating virus. In this Review, we discuss the most recent advances on the mechanisms of protection from disease progression in natural SIV hosts, with emphasis on how they differ from pathogenic HIV/SIV infections of humans and rhesus macaques. These mechanisms include: (i) resolution of immune activation after acute infection, (ii) restricted pattern of target cell infection, and (iii) protection from mother-to-infant transmission. We highlight the areas that should be pursued in future studies, focusing on potential applications for the treatment and prevention of HIV infection.     

Health care policy. U.S. priorities-HIV prevention

One of the scientific anomalies of the AIDS epidemic is the large difference in infection rates across populations. Given limited resources and segregated epidemics, prevention funding should be directed to population segments with high HIV prevalence and incidence. However, recent surveys of U.S. populations indicate that the allocation of prevention dollars is not consistent with the distribution of HIV in the population.     

Preventing AIDS but not HIV-1 infection with a DNA vaccine

Although there has been some success in treating human immunodeficiency virus (HIV) patients with triple drug therapy (highly active antiretroviral therapy or HAART), the best hope for combating AIDS (the disease caused by HIV) could be a combination of drug therapy and vaccination, according to Shen and Siliciano in their Perspective. A new study in rhesus monkeys treated with a DNA vaccine (Barouch et al.) demonstrates that a powerful vaccine-induced CD8(+) cytolytic T cell response reduces the amount of virus in the blood to very low levels preventing the drastic decrease in CD4(+) T helper cells and subsequent immunodeficiency. As the Perspective authors explain, vaccinating HIV patients that are receiving HAART may enable HIV levels to be permanently brought under control such that the drug treatment can eventually be stopped.     

Use of CD134 as a primary receptor by the feline immunodeficiency virus

Feline immunodeficiency virus (FIV) induces a disease similar to acquired immunodeficiency syndrome (AIDS) in cats, yet in contrast to human immunodeficiency virus (HIV), CD4 is not the viral receptor. We identified a primary receptor for FIV as CD134 (OX40), a T cell activation antigen and costimulatory molecule. CD134 expression promotes viral binding and renders cells permissive for viral entry, productive infection, and syncytium formation. Infection is CXCR4-dependent, analogous to infection with X4 strains of HIV. Thus, despite the evolutionary divergence of the feline and human lentiviruses, both viruses use receptors that target the virus to a subset of cells that are pivotal to the acquired immune response.     

Population-level HIV declines and behavioral risk avoidance in Uganda

Uganda provides the clearest example that human immunodeficiency virus (HIV) is preventable if populations are mobilized to avoid risk. Despite limited resources, Uganda has shown a 70% decline in HIV prevalence since the early 1990s, linked to a 60% reduction in casual sex. The response in Uganda appears to be distinctively associated with communication about acquired immunodeficiency syndrome (AIDS) through social networks. Despite substantial condom use and promotion of biomedical approaches, other African countries have shown neither similar behavioral responses nor HIV prevalence declines of the same scale. The Ugandan success is equivalent to a vaccine of 80% effectiveness. Its replication will require changes in global HIV/AIDS intervention policies and their evaluation.     

AIDS--the leading cause of adult death in the West African City of Abidjan, Ivory Coast

In 1988 to 1989, 698 adult cadavers in Abidjan's two largest morgues were studied, representing 38 to 43% of all adult deaths in the city over the study period, and 6 to 7% of annual deaths. Forty-one percent of male and 32% of female cadavers were infected with human immunodeficiency virus (HIV). Fifteen percent of adult male and 13% of adult female annual deaths are due to acquired immunodeficiency syndrome (AIDS). In Abidjan, AIDS is the leading cause of death and years of potential life lost in adult men, followed by unintentional injuries and tuberculosis. In women, AIDS is the second leading cause of death and premature mortality, after deaths related to pregnancy and abortion. AIDS-specific and AIDS-proportional mortality rates may be higher in other African cities where AIDS has been found for a longer time than in Abidjan.     

Specific tropism of HIV-1 for microglial cells in primary human brain cultures

Human immunodeficiency virus (HIV) frequently causes neurological dysfunction and is abundantly expressed in the central nervous system (CNS) of acquired immunodeficiency syndrome (AIDS) patients with HIV encephalitis or myelopathy. The virus is found mostly in cells of the monocyte-macrophage lineage within the CNS, but the possibility of infection of other glial cells has been raised. Therefore, the effects of different HIV-1 and HIV-2 strains were studied in primary cultures of adult human brain containing microglial cells, the resident CNS macrophages, and astrocytes. These cultures could be productively infected with macrophage-adapted HIV-1 isolates but not with T lymphocyte-adapted HIV-1 isolates or two HIV-2 isolates. As determined with a triple-label procedure, primary astrocytes did not express HIV gag antigens and remained normal throughout the 3-week course of infection. In contrast, virus replicated in neighboring microglial cells, often leading to their cell fusion and death. The death of microglial cells, which normally serve immune functions in the CNS, may be a key factor in the pathogenesis of AIDS encephalitis or myelopathy.     

Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms

Human immunodeficiency virus (HIV) is the causative agent of the acquired immune deficiency syndrome (AIDS). A large number of AIDS patients show evidence of neurologic involvement, known as AIDS-related subacute encephalopathy, which has been correlated with the presence of HIV in the brain. In this study, two genetically distinct but related viruses were isolated from one patient from two different sources in the central nervous system: brain tissue and cerebrospinal fluid. Both viruses were found to replicate in peripheral blood lymphocytes, but only virus from brain tissue will efficiently infect macrophage/monocytes. The viruses also differ in their ability to infect a brain glioma explant culture. This infection of the brain-derived cells in vitro is generally nonproductive, and appears to be some form of persistent or latent infection. These results indicate that genetic variation of HIV in vivo may result in altered cell tropisms and possibly implicate strains of HIV with glial cell tropism in the pathogenesis of some neurologic disorders of AIDS.     

AIDS. Origins of HIV

Establishing the date when immunodeficiency viruses were transmitted from nonhuman primates to humans should provide a clue to the origin of the AIDS pandemic. In his Perspective, Hillis discusses an important analysis of the molecular divergence of SIV and HIV genes (Korber et al.). This analysis establishes 1931 as the date of origin of the HIV-1 M-group viruses (the principal cause of the AIDS pandemic). Hillis discusses three possible hypotheses of immunodeficiency virus transmission that are consistent with this date.     

Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS

Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has dramatically increased the incidence of tuberculosis (TB) in subSaharan Africa, where up to 60% of TB patients are coinfected with HIV and each year 200,000 TB deaths are attributable to HIV coinfection. Now HIV threatens control of TB in Asia, Eastern Europe, and Latin America. Antiretroviral (ARV) drugs can prevent TB by preserving immunity, but cohort analysis shows that early therapy, plus high levels of coverage and compliance, will be needed to avert a significant fraction of TB cases. However, ARV drugs could enhance the treatment of TB, and TB programs provide an important entry point for the treatment of HIV/AIDS.     

In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine

The purine analog 2',3'-dideoxyinosine (ddI), which has anti-retroviral activity in vitro was administered for up to 42 weeks to 26 patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex (ARC). Ten of these individuals were AZT-intolerant. Eight dose regimens were studied. The drug was orally bioavailable and penetrated into the cerebrospinal fluid (CSF). Comparatively little evidence of an effect against human immunodeficiency virus (HIV) was seen at the lowest four doses. However, patients in the four highest dose groups (ddI at 1.6 milligrams per kilogram intravenously and then greater than or equal to 3.2 milligrams per kilogram orally at least every 12 hours or higher) had increases in their circulating CD4+ T cells (P less than 0.0005), increased CD4/CD8 T cell ratios (P less than 0.01), and, where evaluable, more than an 80% decrease in serum HIV p24 antigen (P less than 0.05). The patients also had evidence of improved immunologic function, had reduced viremic symptomatology, and gained a mean of 1.6 kilogram with these comparatively infrequent dosing schedules (every 8 or 12 hours). The most notable adverse effects directly attributable to ddI administration at the doses used in this study included increases in serum uric acid (due to hypoxanthine release) and mild headaches and insomnia. These results suggest that serious short-term toxicity at therapeutic doses is not an inherent feature in the profile of agents with clinical anti-HIV activity. Further controlled studies to define the safety and efficacy of this agent may be worth considering.