Course Of Human Immunodeficiency Virus Type 1 Infection Research Articles

Viral Phenotype and T Cell Reactivity in Human Immunodeficiency Virus Type 1-Infected Asymptomatic Men Treated with Zidovudine

The effect of zidovudine on disease progression in asymptomatic human immunodeficiency virus type 1 (HIV-1)-infected men (n = 52) in relation to CD4 T cell numbers, T cell reactivity, and HIV-1 biologic phenotype was studied in a double-blind randomized trial over 2 years. CD4+ cell numbers and T cell reactivity did not differ significantly between the zidovudine- and placebo-treated groups, except for a transient improvement of both parameters in the zidovudine-treated group during the first 9 months. A marked differential efficacy of zidovudine was observed depending on the HIV-1 phenotype present. Zidovudine did not prevent the emergence of high-replicating syncytium-inducing (SI) variants, and clinical progression was observed in persons with SI variants despite zidovudine treatment. In contrast to nontreated HIV-1-infected asymptomatic persons, zidovudine-treated men who did not develop SI variants did not progress to AIDS. The beneficial effect of zidovudine during the asymptomatic phase may be mainly limited to persons who do not develop SI variants in the course of HIV-1 infection.

Prognostic Value of HIV-1 Syncytium-Inducing Phenotype for Rate of CD4+ Cell Depletion and Progression to AIDS

To investigate the relation between detection of syncytium-inducing (SI), human immunodeficiency virus type 1 (HIV-1) variants, rate of CD4+ cell decline, and clinical progression. Prospective study during a 2.5-year follow-up period; cohort study with pairwise matched controls. The Amsterdam cohort study on the course of HIV-1 infection in homosexual men. Asymptomatic HIV-1 infected men (n = 225) were tested for the presence of SI variants and were studied prospectively for CD4+ cell decline and clinical progression. In addition, 45 men with a defined moment of appearance of SI variants and 45 matched controls without SI variants were compared for CD4+ cell decline. Syncytium-inducing variants were detected by cocultivation of peripheral blood mononuclear cells with the MT-2 T-cell line. During a 30-month period, 70.8% of the men with SI variants progressed to AIDS, compared with 15.8% of men without SI variants at entry (P < 0.0001). Multivariable Cox proportional hazard analysis, controlling for CD4+ cell count and HIV-p24 antigenemia, showed a relative hazard for SI variants of 6.7 (95% Cl, 3.5 to 12.7). In the matched control study, before the appearance of SI variants, CD4+ cell counts of 45 men with SI variants and their controls were compared. Syncytium-inducing variants emerged at a mean CD4+ cell count of 0.48 x 10(9)/L(Cl, 0.42 to 0.54), coinciding with the onset of a threefold increased rate of CD4+ cell decline. Men developing AIDS with SI variants had decreased CD4+ cell counts (0.08 x 10(9)/L; 95% Cl, 0.05 to 0.12) at the time of diagnosis compared with persons progressing to AIDS without SI variants (0.25 x 10(9)/L 95% Cl, 0.15 to 0.41) (P = 0.0035]. The HIV-1 biological phenotype is a practical, binary marker for progression to AIDS, which is independent of decreased CD4+ cell counts and antigenemia. Appearance of SI variants, occurring 2 years before progression to AIDS on the average, is predictive for a significantly increased rate of CD4+ cell decline.

Perinatal AIDS: drugs of abuse and transplacental infection.

The number of children infected by the human immunodeficiency virus type-1 (HIV-1) who develop the acquired immunodeficiency syndrome (AIDS) continues to increase. While some children become infected after birth and others at the time of parturition, a significant percentage are infected during gestation and there is a positive correlation between maternal illicit intravenous drug use and fetal HIV-1 infection. Drugs can contribute in, at least, four ways to vertical transmission of HIV-1. These four ways are divisible into 2 main categories that are comprised of both direct and indirect mechanisms. For example, drugs of abuse can have a direct effect on the maternal-fetal interface. Cocaine is associated with vasculitis. If this occurs as a placentitis or chorioamnionitis, it can alter the permeability of these barriers to maternal blood and increase the number of potentially infected inflammatory cells in this tissue and as a result in the fetus. Another direct mechanism wherein drugs of abuse can increase the probability that a fetus will become infected is via an inflammatory reaction such as a vasculitis in the fetus rendering it more susceptible to viral infection. Drugs can also affect the course of HIV-1 infection via indirect mechanisms. An example of this may be by modulating the female immune system. This effect can exacerbate the woman's immunodeficiency and accelerate opportunistic infections. For example, cytomegalovirus infection resulting in placentitis might facilitate fetal HIV-1 infection. Lastly, a similar type of indirect mechanism can be postulated for the fetus wherein its developing immune system can be adversely effected.(ABSTRACT TRUNCATED AT 250 WORDS)

Monocytotropic human immunodeficiency virus type 1 (HIV-1) variants detectable in all stages of HIV-1 infection lack T-cell line tropism and syncytium-inducing ability in primary T-cell culture

We previously demonstrated a correlation between the presence of syncytium-inducing (SI) human immunodeficiency virus type 1 (HIV-1) variants showing tropism for cell line H9 and the occurrence of rapid CD4 cell decline and progression to AIDS. In contrast, in stable asymptomatic individuals, we detected only isolates with low replication rates that were non-syncytium-inducing (NSI) and nontropic for the H9 cell line. Here, we investigated the monocytotropism of established HIV-1 isolates with a panel of isolates and with biological HIV-1 clones with distinct phenotypes. Moreover, the prevalence and biological phenotypes of monocytotropic HIV-1 variants in the course of HIV-1 infection were analyzed in comparative primary isolation studies on peripheral blood lymphocytes (PBL) and monocyte-derived macrophages (MDM). In cell-free infection studies with MDM from eight blood donors, 13 of 17 NSI isolates but only 4 of 14 SI isolates were able to infect MDM. NSI isolates also infected significantly more different donors than SI variants (median, 3 of 8 versus 0 of 8). This enhanced monocytotropism of NSI isolates was confirmed in experiments with biological HIV-1 clones with distinct phenotypes recovered from the same donor. To investigate the prevalence and biological phenotypes of monocytotropic variants in different stages of HIV-1 infection, sequential isolates from peripheral blood mononuclear cell samples from nine asymptomatic individuals, five of whom progressed to AIDS and seven of whom had a known time of seroconversion, were recovered by cocultivation with both PBL and MDM. Monocytotropic variants were obtained from 37 of 42 time points. All monocytotropic variants were NSI in PBL culture and non-T-cell-line tropic, even when SI, T-cell-line-tropic HIV-1 variants could be recovered from the same patient sample by cocultivation with PBL. We conclude that monocytotropic HIV-1 variants mostly have an NSI phenotype in PBL and, in contrast to SI variants, are present at all stages of HIV-1 infection. These results suggest an important role for monocytotropic variants in the persistence of HIV-1 infection.

Laboratory Methods in the Diagnosis and Prognostic Staging of infection with Human Immunodificiency Virus Type 1

Laboratory evaluation of infection with human immunodeficiency virus type 1 (HIV-1) may involve detection of antibodies to HIV-1, direct detection of HIV-1 itself, and measurement of an individual's immunologic status at the time of presentation. The ELISA is currently the preferred initial screening test, although a variety of other rapid immunoassays have also been developed. Methods defining the antigenic specificity of the antibody response, such as the western blot, have become standard confirmatory tests in this setting. CD4+ cell enumeration and the HIV-1 antigen capture assay are useful in predicting the course of HIV-1 infection and in monitoring antiretroviral therapies. Newer techniques of HIV-1 co-cultivation permit the characterization of viral isolates and the stratification of patients and facilitate monitoring of the effects of antiretroviral agents. The polymerase chain reaction is of value in identifying HIV-1 infection in individuals with inconclusive serologic results. Judicious use of other laboratory tests, including surrogate markers such as beta 2-microglobulin, also provides prognostic information potentially useful in clinical management of HIV-1-infected patients.

Expanded HIV-1 Cellular Tropism by Phenotypic Mixing with Murine Endogenous Retroviruses

In view of the current interest in in vivo murine models for acquired immunodeficiency syndrome (AIDS), the interaction between human immunodeficiency virus type 1 (HIV-1) and endogenous murine leukemia virus (MuLV)-related retroviruses was investigated with a human leukemic T cell line (PF-382x) that acquired xenotropic MuLV (X-MuLV) after in vivo passage in immunosuppressed mice. Despite similar levels of membrane CD4 expression and HIV-1 125I-labeled gp 120 binding, a dramatic acceleration in the time course of HIV-1 infection was observed in PF-382x compared to its X-MuLV-negative counterpart (PF-382). Moreover, PF-382 cells coinfected by X-MuLV and HIV-1 generated a progeny of phenotypically mixed viral particles, enabling HIV-1 to productively infect a panel of CD4- human cells, including B lymphoid cells and purified normal peripheral blood CD4-/CD8+ T lymphocytes. Mixed viral phenotypes were also produced by human CD4+ T cells coinfected with an amphotropic MuLV-related retrovirus (A-MuLV) and HIV-1. These data show that endogenous MuLV acquired by human cells transplanted into mice can significantly interact with HIV-1, thereby inducing important alterations of HIV-1 biological properties.

Antibody-dependent enhancement of human immunodeficiency virus type 1 (HIV-1) infection in vitro by serum from HIV-1-infected and passively immunized chimpanzees.

Based on recent reports of antibody-dependent enhancement of human immunodeficiency virus type 1 (HIV-1) infection in vitro by serum from HIV-1-infected humans, sera from HIV-1 antibody-positive chimpanzees (Pan troglodytes) was evaluated for enhancing activity in an in vitro infection assay that uses MT-2 cells (a human lymphoblastoid cell line). Although fresh chimpanzee serum was found to have pronounced infection-enhancing properties in the absence of antibody to HIV-1, this effect was abolished by heat inactivation (57 degrees C, 1 hr) or treatment with cobra venom anticomplementary protein. Heat-inactivated, HIV-1 antibody-positive chimpanzee serum could enhance HIV-1 infection of MT-2 cells in vitro when combined with fresh, normal human serum. By serial serum samples from three HIV-1-infected chimpanzees, HIV-1 antibody-positive chimpanzees are shown to develop enhancing antibodies early in infection (2 mo postchallenge), whereas neutralizing antibodies develop later. Over the course of HIV-1 infection, this enhancing activity decreases while neutralizing activity increases, suggesting a possible role for enhancing and neutralizing activities in HIV-1 pathogenesis. The enhancing activity of an IgG fraction used to passively immunize chimpanzees against HIV-1 infection is shown to be present at dilutions as high as 1:65,000, offering an interesting possible reason for the failure of passive immunization to protect chimpanzees from HIV infection. These results suggest that serum from HIV-1-immunized chimpanzees might be tested to determine whether current HIV-1 candidate vaccines induce production of antibodies that mediate antibody-dependent enhancement of HIV-1 infection in this in vitro assay.

Infection with human immunodeficiency virus in the Pittsburgh transplant population. A study of 583 donors and 1043 recipients, 1981-1986.

We performed a retrospective serologic survey of 583 organ donors and 1043 transplant recipients for antibodies to human immunodeficiency virus type 1 (HIV-1). Two (0.34%) of the 583 donors and 18 (1.7%) of the 1043 recipients had HIV-1 antibodies by enzyme immunoassay and by Western blot. Two of 5 seropositive recipients tested also had blood cultures positive for HIV-1. Seven (0.7%) of the 1043 transplant recipients had antibodies to HIV-1 before transplantation; 2 of these had hemophilia A, and 5 had previous transfusions. Eleven (1.3%) of 860 recipients followed for 45 days or more seroconverted to HIV-1 a mean of 96 days after transplantation. Likely sources of HIV-1 infection for 3 of these 11 recipients included a seropositive organ donor in 1 patient and high-risk blood donors in 2 patients. A definite source of HIV-1 infection was not found for the other 8 recipients, 3 of whom seroconverted to HIV-1 after institution of blood donor screening for HIV-1 antibodies. Seroconversion to HIV-1 was less common in kidney recipients than in liver, heart, or multiple-organ recipients (P less than 0.02). Nine (50%) of the 18 HIV-1 seropositive transplant recipients died a mean of 6 months after transplant surgery, and 9 (50%) are still alive a mean of 43 months after transplantation. AIDS-like illnesses occurred in 3 of the dead and 1 of the living patients and included pneumocystis pneumonia (3 cases), miliary tuberculosis (1 case), and recurrent cytomegalovirus infection (1 case). These data suggest that the course of HIV-1 infection is not more severe in transplant recipients receiving cyclosporine than in other hosts and that, despite screening of blood and organ donors, a small number of transplant recipients will become infected with HIV-1.