New human T-lymphotropic retrovirus related to simian T-lymphotropic virus type III (STLV-IIIAGM)

This report describes serologic evidence for a virus similar to that known as simian T-lymphotropic virus type III of African Green monkeys (STLV-IIIAGM) infecting apparently healthy people in Senegal, West Africa, and the isolation of virus from these individuals. Serum samples from selected healthy West African people showed unusual serologic profiles when tested with antigens of HTLV-III/LAV, the etiologic agent of AIDS, and of STLV-IIIAGM. The samples reacted strongly with all of the major viral antigens of STLV-IIIAGM but showed variable or no reactivity with the major viral antigens of HTLV-III/LAV by radioimmunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A new human T-lymphotropic virus (HTLV-IV) isolated from these people was grown in vitro and shown to have retroviral type particles, growth characteristics, and major viral proteins similar to those of the STLV-III and HTLV-III/LAV group of retroviruses. The gp120/160, gp32, p64, p55, p53, p24, and p15 proteins precipitated were the same size as and reactive with STLV-IIIAGM proteins. The serologic data suggest that this virus shares more common epitopes with STLV-IIIAGM than with the prototype HTLV-III/LAV that infects people in the United States and Europe. Further study of this virus and of the origin of the HTLV-III/LAV group of viruses may expand our understanding of the human AIDS virus.     

Genomic diversity of human T-lymphotropic virus type III (HTLV-III)

The DNA genomes of human T-lymphotropic virus type III (HTLV-III) isolated from 18 individuals with AIDS or who were at risk for AIDS were evaluated for evidence of variation. Although all of the 18 viral DNA's hybridized throughout their entire genomes to a full-length cloned probe of the original HTLV-III isolate, each of the 18 isolates showed a different restriction enzyme pattern. The number of restriction site differences between isolates ranged from only 1 site in 23 to at least 16 sites in 31. No particular viral genotype was associated with a particular disease state and 2 of the 18 patients had evidence of concurrent infection by more than one viral genotype. Propagation of three different viral isolates in vitro for up to 9 months did not lead to detectable changes in their restriction patterns. These findings indicate that different isolates of HTLV-III comprise a spectrum of highly related but distinguishable viruses and have important implications regarding the pathogenicity of HTLV-III and attempts to develop effective diagnostic, therapeutic, and preventive measures for this virus.     

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.     

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.     

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.     

West African HIV-2-related human retrovirus with attenuated cytopathicity

Clinical and seroepidemiological studies in West Africa indicate that human immunodeficiency virus type 2 (HIV-2) is widespread and associated with immunodeficiency states of variable degree. In this study, an isolate of HIV-2 from a patient in Senegal was molecularly cloned and characterized. This isolate (HIV-2ST) was shown by hybridization and restriction enzyme analysis to be more related to the prototype HIV-2ROD than to other human or primate retroviruses. Cultures of HIV-2ST showed genotypic polymorphism, and clones of the virus had transmembrane envelope glycoproteins of 30 and 42 kilodaltons. Unlike other immunodeficiency viruses, HIV-2ST did not cause cell death or induce cell fusion in peripheral blood lymphocytes or in any of four CD4+ cell lines tested. Although HIV-2ST entered cells by a CD4-dependent mechanism and replicated actively, cell-free transmission of the virus was retarded at the level of cell entry. These findings suggest that immunodeficiency viruses prevalent in West African populations are members of the HIV-2 virus group and that certain strains of this virus have attenuated virulence.     

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.     

Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS

In cats, infection with T-lymphotropic retroviruses can cause T-cell proliferation and leukemia or T-cell depletion and immunosuppression. In humans, some highly T4 tropic retroviruses called HTLV-I can cause T-cell proliferation and leukemia. The subgroup HTLV-II also induces T-cell proliferation in vitro, but its role in disease is unclear. Viruses of a third subgroup of human T-lymphotropic retroviruses, collectively designated HTLV-III, have been isolated from cultured cells of 48 patients with acquired immunodeficiency syndrome (AIDS). The biological properties of HTLV-III and immunological analyses of its proteins show that this virus is a member of the HTLV family, and that it is more closely related to HTLV-II than to HTLV-I. Serum samples from 88 percent of patients with AIDS and from 79 percent of homosexual men with signs and symptoms that frequently precede AIDS, but from less than 1 percent of heterosexual subjects, have antibodies reactive against antigens of HTLV-III. The major immune reactivity appears to be directed against p41, the presumed envelope antigen of the virus.     

Isolation of a new human retrovirus from West African patients with AIDS

The etiological agent of AIDS, LAV/HTLV-III, is common in Central Africa but is not endemic in other areas of that continent. A novel human retrovirus, distinct from LAV/HTLV-III, has now been isolated from two AIDS patients from West Africa. Partial characterization of this virus revealed that it has biological and morphological properties very similar to LAV but that it differs in some of its antigenic components. Although the core antigens may share some common epitopes, the West African AIDS retrovirus and LAV differ substantially in their envelope glycoproteins. The envelope antigen of the West African virus can be recognized by serum from a macaque with simian AIDS infected by the simian retrovirus termed STLV-IIImac, suggesting that the West African AIDS virus may be more closely related to this simian virus than to LAV. Hybridization experiments with LAV subgenomic probes further established that this new retrovirus, here referred to as LAV-II, is distantly related to LAV and distinct from STLV-IIImac.     

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.     

HTLV-III in the semen and blood of a healthy homosexual man

Human T-lymphotropic virus type III (HTLV-III) is the probable etiologic agent for the acquired immune deficiency syndrome (AIDS). HTLV-III was isolated from semen and blood of a healthy homosexual man whose serum contains antibodies to HTLV-III. The finding of virus in semen supports epidemiologic data that suggest that AIDS can be transmitted sexually. In addition, the demonstration of HTLV-III in the blood and semen of a healthy individual establishes an asymptomatic, virus-positive carrier state which may be important in the dissemination of HTLV-III and, consequently, AIDS.     

Isolation of a T-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome

A highly T-lymphotropic virus was isolated from cats in a cattery in which all the animals were seronegative for feline leukemia virus. A number of cats in one pen had died and several had an immunodeficiency-like syndrome. Only 1 of 18 normal cats in the cattery showed serologic evidence of infection with this new virus, whereas 10 of 25 cats with signs of ill health were seropositive for the virus. Tentatively designated feline T-lymphotropic lentivirus, this new feline retrovirus appears to be antigenically distinct from human immunodeficiency virus. There is no evidence for cat-to-human transmission of the agent. Kittens experimentally infected by way of blood or plasma from naturally infected animals developed generalized lymphadenopathy several weeks later, became transiently febrile and leukopenic, and continued to show a generalized lymphadenopathy 5 months after infection.     

Genetic variation in HTLV-III/LAV over time in patients with AIDS or at risk for AIDS

In a study of genetic variation in the AIDS virus, HTLV-III/LAV, sequential virus isolates from persistently infected individuals were examined by Southern blot genomic analysis, molecular cloning, and nucleotide sequencing. Four to six virus isolates were obtained from each of three individuals over a 1-year or 2-year period. Changes were detected throughout the viral genomes and consisted of isolated and clustered nucleotide point mutations as well as short deletions or insertions. Results from genomic restriction mapping and nucleotide sequence comparisons indicated that viruses isolated sequentially had evolved in parallel from a common progenitor virus. The rate of evolution of HTLV-III/LAV was estimated to be at least 10(-3) nucleotide substitutions per site per year for the env gene and 10(-4) for the gag gene, values a millionfold greater than for most DNA genomes. Despite this relatively rapid rate of sequence divergence, virus isolates from any one patient were all much more related to each other than to viruses from other individuals. In view of the substantial heterogeneity among most independent HTLV-III/LAV isolates, the repeated isolation from a given individual of only highly related viruses raises the possibility that some type of interference mechanism may prevent simultaneous infection by more than one major genotypic form of the virus.     

Norwalk virus genome cloning and characterization

Major epidemic outbreaks of acute gastroenteritis result from infections with Norwalk or Norwalk-like viruses. Virus purified from stool specimens of volunteers experimentally infected with Norwalk virus was used to construct recombinant complementary DNA (cDNA) and derive clones representing most of the viral genome. The specificity of the clones was shown by their hybridization with post- (but not pre-) infection stool samples from volunteers infected with Norwalk virus and with purified Norwalk virus. A correlation was observed between the appearance of hybridization signals in stool samples and clinical symptoms of acute gastroenteritis in volunteers. Hybridization assays between overlapping clones, restriction enzyme analyses, and partial nucleotide sequence information of the clones indicated that Norwalk virus contains a single-stranded RNA genome of positive sense, with a polyadenylated tail at the 3' end and a size of at least 7.5 kilobases. A consensus amino acid sequence motif typical of viral RNA-dependent RNA polymerases was identified in one of the Norwalk virus clones. The availability of Norwalk-specific cDNA and the new sequence information of the viral genome should permit the development of sensitive diagnostic assays and studies of the molecular biology of the virus.     

Evidence for exposure to HTLV-III in Uganda before 1973

Fifty of 75 serum samples collected in the West Nile district of Uganda between August 1972 and July 1973 contained antibodies reactive with human T-cell leukemia (lymphotropic) virus type 3 (HTLV-III; mean titer, 601), while 12 of 75 samples were positive in a similar test for HTLV type 1 (HTLV-1) antibodies (mean titer, 236). The samples were screened by enzyme-linked immunosorbent assay and positive results were confirmed by a newly developed unlabeled antibody-peroxidase procedure with enhanced sensitivity for detection of antibody binding to immunoblots of HTLV-III antigen, demonstrating antibodies to proteins with molecular weights of 24,000, 41,000, and 76,000 in nearly all positive samples. Analysis of titration data indicated enhanced titers of antibody against HTLV-III and HTLV-I when coinfection occurred. The high prevalence and relatively low titers [compared to serum from patients with acquired immune deficiency syndrome (AIDS)] of antibodies recognizing HTLV-III proteins in sera from this population at a time that may predate or coincide with the appearance or spread of the AIDS agent (HTLV-III) suggest that the virus detected may have been a predecessor of HTLV-III or is HTLV-III itself but existing in a population acclimated to its presence. It further suggests an African origin of HTLV-III.     

Synthetic peptide immunoassay distinguishes HIV type 1 and HIV type 2 infections

Efforts to solve the epidemiologic puzzle of AIDS in Africa are complicated by the presence of multiple human retroviruses. Simple serologic tests that unambiguously distinguish among infections by these retroviruses are essential. To that end, a partially conserved immunoreactive epitope was identified in the transmembrane glycoproteins of human immunodeficiency viruses (HIV) types 1 and 2. Synthetic peptides derived from these conserved domains were used in sensitive and specific immunoassays that detect antibodies in sera from patients infected with HIV-1 or HIV-2. By making single amino acid substitutions in the HIV-1 peptide, it was possible to demonstrate HIV-1 strain-specific antibody responses to this epitope. Such custom-designed peptides synthesized from this domain are likely to detect newly discovered HIV types, define infection with specific HIV strains, and allow detection of group-common antibodies.     

Proviral DNA of a retrovirus, human T-cell leukemia virus, in two patients with AIDS

The acquired immune deficiency syndrome (AIDS) is characterized by T-lymphocyte dysfunction and is frequently accompanied by opportunistic infections and Kaposi's sarcoma. Human T-cell leukemia virus (HTLV) is associated with T-cell malignancies and can transform T lymphocytes in vitro. In an attempt to find evidence of HTLV infection in patients with AIDS, DNA from samples of peripheral blood lymphocytes from 33 AIDS patients was analyzed by Southern blot-hybridization with a radiolabeled cloned HTLV DNA probe. Analysis of DNA from both the fresh (uncultured) lymphocytes and from T cells cultured with T-cell growth factor revealed the presence of integrated HTLV proviral sequences in lymphocytes from two of the patients, both of whom had antibody to HTLV. The proviral sequences could not be detected in blood samples obtained from these individuals at a later date, consistent with the possibility that the population of infected cells had become depleted.     

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.     

Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders

A novel human B-lymphotropic virus (HBLV) was isolated from the peripheral blood leukocytes of six individuals: two HTLV-III seropositive patients from the United States (one with AIDS-related lymphoma and one with dermatopathic lymphadenopathy), three HTLV-III seronegative patients from the United States (one with angioimmunoblastic lymphadenopathy, one with cutaneous T-cell lymphoma, and one with immunoblastic lymphoma), and one HTLV-III seronegative patient with acute lymphocytic leukemia from Jamaica. All six isolates were closely related by antigenic analysis, and sera from all six virus-positive patients reacted immunologically with each virus isolate. In contrast, only four sera from 220 randomly selected healthy donors and none from 12 AIDS patients without associated lymphoma were seropositive. The virus selectively infected freshly isolated human B cells and converted them into large, refractile mono- or binucleated cells with nuclear and cytoplasmic inclusion bodies. HBLV is morphologically similar to viruses of the herpesvirus family but is readily distinguishable from the known human and nonhuman primate herpesviruses by host range, in vitro biological effects, and antigenic features.