Antigens on HTLV-infected cells recognized by leukemia and AIDS sera are related to HTLV viral glycoprotein

Cross-reactive antigens of molecular size of 61,000 to 68,000 daltons are found on the surface of human cells infected by human T-cell leukemia-lymphoma virus (HTLV). They are recognized by antibodies from patients with adult T-cell leukemias and lymphomas, from healthy carriers of HTLV, and from patients with the acquired immunodeficiency syndrome (AIDS). The latter finding has been one of the major reasons for suggesting an association of HTLV with AIDS. However, whether these antigens are of cellular or viral origin has not been clear. These antigens have now been shown to be associated with the presence of viral proteins in the cells, and a cross-reactive glycoprotein of molecular size of 46,000 daltons has been found to be a consistent structural part of viruses purified from several HTLV-producer cell lines. The findings thus suggest a viral (HTLV) origin of these antigens.     

AIDS as a zoonosis: scientific and public health implications

Evidence of simian immunodeficiency virus (SIV) infection has been reported for 26 different species of African nonhuman primates. Two of these viruses, SIVcpz from chimpanzees and SIVsm from sooty mangabeys, are the cause of acquired immunodeficiency syndrome (AIDS) in humans. Together, they have been transmitted to humans on at least seven occasions. The implications of human infection by a diverse set of SIVs and of exposure to a plethora of additional human immunodeficiency virus-related viruses are discussed.     

Chimpanzee reservoirs of pandemic and nonpandemic HIV-1

Human immunodeficiency virus type 1 (HIV-1), the cause of human acquired immunodeficiency syndrome (AIDS), is a zoonotic infection of staggering proportions and social impact. Yet uncertainty persists regarding its natural reservoir. The virus most closely related to HIV-1 is a simian immunodeficiency virus (SIV) thus far identified only in captive members of the chimpanzee subspecies Pan troglodytes troglodytes. Here we report the detection of SIVcpz antibodies and nucleic acids in fecal samples from wild-living P. t. troglodytes apes in southern Cameroon, where prevalence rates in some communities reached 29 to 35%. By sequence analysis of endemic SIVcpz strains, we could trace the origins of pandemic (group M) and nonpandemic (group N) HIV-1 to distinct, geographically isolated chimpanzee communities. These findings establish P. t. troglodytes as a natural reservoir of HIV-1.     

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.     

Human T-lymphotropic virus type 4 and the human immunodeficiency virus in West Africa

A new human T-lymphotropic virus (HTLV-4) was recently described in healthy people from Senegal. This virus has many properties in common with members of the human T-lymphotropic viruses, particularly the human immunodeficiency virus or HIV, the etiologic agent of acquired immune deficiency syndrome (AIDS), but does not appear to be associated with immunodeficiency-related disorders. In the present study, serum samples were obtained from 4248 individuals from six West African countries, including Senegal, Guinea, Guinea Bissau, Mauritania, Burkina Faso, and Ivory Coast. These samples, collected during 1985-1987, were from people categorized as healthy control, sexually active risk, and disease populations. All samples were analyzed for reactivity to HTLV-4 and HIV by radioimmunoprecipitation-sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. Evidence for HTLV-4 infection was found in five of the six countries. The seroprevalence varied markedly from country to country. Healthy sexually active individuals in the risk category had the highest levels of HTLV-4 infection compared to individuals in the healthy control category and the disease category, the latter including AIDS patients. The seroprevalence of HIV infection in most of these countries was quite low, although tightly associated with the rare cases of AIDS. The biology of HTLV-4 infection thus differs from that of HIV in Central Africa or the United States and Europe. The presence of these viruses and their different pathogenicities in several countries of West Africa indicate the necessity for serologic assays that will distinguish between them. Further studies of their origin and distribution as well as of their biology will be important in advancing our understanding of AIDS.     

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.     

Molecular analyses of oral polio vaccine samples

It has been suggested that the human immunodeficiency virus (HIV), and thus the acquired immunodeficiency syndrome (AIDS) it causes, was inadvertently introduced to humans by the use of an oral polio vaccine (OPV) during a vaccination campaign launched by the Wistar Institute, Philadelphia, PA, USA, in the Belgian Congo in 1958 and 1959. The "OPV/AIDS hypothesis" suggests that the OPV used in this campaign was produced in chimpanzee kidney epithelial cell cultures rather than in monkey kidney cell cultures, as stated by H. Koprowski and co-workers, who produced the OPV. If chimpanzee cells were indeed used, this would lend support to the OPV/AIDS hypothesis, since chimpanzees harbor a simian immunodeficiency virus, widely accepted to be the origin of HIV-1. We analyzed several early OPV pools and found no evidence for the presence of chimpanzee DNA; by contrast, monkey DNA is present.     

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.     

Generation of simian-tropic HIV-1 by restriction factor evasion

Because HIV-1 does not infect most nonhuman primates, animal modeling of human HIV infection and AIDS has primarily consisted of experimentally infecting macaques with related simian immunodeficiency viruses (SIVMAC). However, the usefulness of such models is limited by the substantial divergence between SIVMAC and HIV-1. We derived an HIV-1-based virus that includes only small portions of SIVMAC yet replicates robustly in both transformed and primary rhesus macaque T cells. Derivation of simian-tropic HIV-1 (stHIV-1) has important implications for understanding primate lentivirus zoonosis and should allow the development of improved animal models for studies of AIDS and the evaluation of vaccines and treatments.     

Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS

A cell system was developed for the reproducible detection of human T-lymphotropic retroviruses (HTLV family) from patients with the acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that frequently precede AIDS (pre-AIDS). The cells are specific clones from a permissive human neoplastic T-cell line. Some of the clones permanently grow and continuously produce large amounts of virus after infection with cytopathic (HTLV-III) variants of these viruses. One cytopathic effect of HTLV-III in this system is the arrangement of multiple nuclei in a characteristic ring formation in giant cells of the infected T-cell population. These structures can be used as an indicator to detect HTLV-III in clinical specimens. This system opens the way to the routine detection of HTLV-III and related cytopathic variants of HTLV in patients with AIDS or pre-AIDS and in healthy carriers, and it provides large amounts of virus for detailed molecular and immunological analyses.     

Biologic features of HIV-1 that correlate with virulence in the host

Individuals infected with the human immunodeficiency virus type 1 (HIV-1) may be asymptomatic or have AIDS-related complex or the acquired immuno deficiency syndrome (AIDS). Little is known about the factors that influence progression of infection to AIDS. In this study of isolates of HIV-1 obtained at intervals during the infection of four individuals, the development of disease was found to be correlated with the emergence of HIV-1 variants that were more cytopathic in vitro as the disease progressed and that replicated more efficiently in a wide variety of different human cells. The biologic properties of HIV-1 in vitro thus appear to reflect its virulence in the host. Further studies of such sequentially isolated viruses may lead to the identification of viral genes that govern pathogenesis.     

HIV-1 production from infected peripheral blood T cells after HTLV-I induced mitogenic stimulation

The human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type I (HTLV-I) are two distinct human retroviruses that infect T cells. Recent epidemiologic studies have identified a cohort of individuals that are coinfected with both viruses. It is reported here that human peripheral blood leukocytes infected with HIV-1 in vitro can be induced to produce large quantities of HIV-1 after mitogenic stimulation by noninfectious HTLV-I virions. It is also shown that HTLV-I virions may exert this effect prior to, immediately following, or well after the cells are infected with HIV-1. These results provide further impetus for epidemiologic studies of dually infected individuals to determine whether HTLV-I may act as a cofactor for acquired immunodeficiency syndrome (AIDS).     

Searching for the epidemic's origins

Theories about the origin of AIDS all suffer from a dearth of data. For more than a decade, researchers have recognized the close genetic links between SIV from sooty mangabeys and HIV-2, a type of the virus that is mostly confined to west African countries, but to date, there are scant data that closely link HIV-1, the predominant human AIDS virus, to SIVs found in primates.     

Immunodeficiency and clonal growth of target cells induced by helper-free defective retrovirus

The murine acquired immunodeficiency syndrome is induced by a defective retrovirus. To study the role of virus replication in this disease, helper-free stocks of defective Duplan virus were produced. These stocks were highly pathogenic in absence of detectable replicating murine leukemia viruses (MuLVs) other than xenotropic MuLV. They induced expansion of the infected cell population (over 1000-fold), and this cell expansion was oligoclonal in origin and, most likely, arose through cell division. These results suggest that this defective virus is oncogenic, inducing a primary neoplasia associated with an acquired immunodeficiency syndrome as a paraneoplastic syndrome. These data emphasize the need to determine whether virus replication is necessary for the progression of other immunodeficiency diseases, including acquired immunodeficiency syndrome, and whether these diseases also represent paraneoplastic syndromes.     

Timing the ancestor of the HIV-1 pandemic strains

HIV-1 sequences were analyzed to estimate the timing of the ancestral sequence of the main group of HIV-1, the strains responsible for the AIDS pandemic. Using parallel supercomputers and assuming a constant rate of evolution, we applied maximum-likelihood phylogenetic methods to unprecedented amounts of data for this calculation. We validated our approach by correctly estimating the timing of two historically documented points. Using a comprehensive full-length envelope sequence alignment, we estimated the date of the last common ancestor of the main group of HIV-1 to be 1931 (1915-41). Analysis of a gag gene alignment, subregions of envelope including additional sequences, and a method that relaxed the assumption of a strict molecular clock also supported these results.     

Induction of AIDS in rhesus monkeys by molecularly cloned simian immunodeficiency virus

Better understanding of the pathogenesis of acquired immunodeficiency syndrome (AIDS) would be greatly facilitated by a relevant animal model that uses molecularly cloned virus of defined sequence to induce the disease. Such a system would also be of great value for AIDS vaccine research. An infectious molecular clone of simian immunodeficiency virus (SIV) was identified that induces AIDS in common rhesus monkeys in a time frame suitable for laboratory investigation. These results provide another strong link in the chain of evidence for the viral etiology of AIDS. More importantly, they define a system for molecular dissection of the determinants of AIDS pathogenesis.     

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.     

Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV-III) associated with AIDS

The two main subgroups of the family of human T-lymphotropic retroviruses (HTLV) that have previously been characterized are known as HTLV-I and HTLV-II. Both are associated with certain human leukemias and lymphomas. Cell surface antigens (p61 and p65) encoded by HTLV-I are frequently recognized, at low titers, by antibodies in the serum of patients with acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that precede AIDS (pre-AIDS). This suggests an involvement of HTLV in these disorders. Another subgroup of HTLV, designated HTLV-III, has now been isolated from many patients with AIDS and pre-AIDS. In the studies described in this report, virus-associated antigens in T-cell clones permanently producing HTLV-III were subjected to biochemical and immunological analyses. Antigens of HTLV-III, specifically detected by antibodies in serum from AIDS or pre-AIDS patients and revealed by the Western blot technique, are similar in size to those found in other subgroups of HTLV. They include at least three serologically unrelated antigenic groups, one of which is associated with group-specific antigens (p55 and P24) and another with envelope-related (p65) proteins, while the antigens in the third group are of unknown affiliation. The data show that HTLV-III is clearly distinguishable from HTLV-I and HTLV-II but is also significantly related to both viruses. HTLV-III is thus a true member of the HTLV family.