Showing papers by "Robert M. Grant published in 2000"

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

Abstract: 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.

Sustained CD4+ T Cell Response after Virologic Failure of Protease Inhibitor-Based Regimens in Patients with Human Immunodeficiency Virus Infection

Abstract: The relationship between plasma human immunodeficiency virus (HIV) RNA levels and peripheral CD4+ T cell counts was examined in 380 HIV-infected adults receiving long-term protease inhibitor therapy. Patients experiencing virologic failure (persistent HIV RNA >500 copies RNA/mL) generally had CD4+ T cell counts that remained greater than pretherapy baseline levels, at least through 96 weeks of follow-up. The CD4+ T cell response was directly and independently related to degree of viral suppression below the pretreatment baseline. For any given HIV RNA level measured 12 weeks after virologic failure, subsequent CD4+ T cell decline was slower in patients receiving a protease inhibitor-based regimen than in a historical control group of untreated patients. These observations suggest that transient or partial declines in plasma HIV RNA levels can have sustained effects on CD4+ T cell levels.

Cytopathicity of Human Immunodeficiency Virus Type 2 (HIV-2) in Human Lymphoid Tissue Is Coreceptor Dependent and Comparable to That of HIV-1

Abstract: Epidemiological studies have shown that human immunodeficiency virus type 2 (HIV-2) is markedly less pathogenic than HIV-1 in vivo. Individuals infected with HIV-2 exhibit a remarkably slow rate of disease development, and these clinical properties have been attributed presumptively to an “attenuated” phenotype of HIV-2 itself. Here, we investigated the impact of coreceptor usage on the cytopathicity of HIV-2 and compared its pathogenic potential with that of HIV-1 in a unique human lymphoid histoculture model. We found that HIV-2 strains, as well as closely related simian immunodeficiency viruses (SIV), displayed mildly or highly aggressive cytopathic phenotypes depending on their abilities to use the coreceptor CCR5 or CXCR4, respectively. A side-by-side comparison of primary X4 HIV-1 and HIV-2 strains revealed similar, high degrees of cytopathicity induced by both HIV types. Furthermore, we found that HIV-2 coreceptor specificity for CCR5 and CXCR4 determined the target cell population for T-cell depletion in lymphoid tissue. Finally, utilization of the alternate coreceptors BOB and Bonzo did not significantly increase the cytopathic properties of HIV-2. These findings demonstrate that coreceptor preference is a key regulator of target cell specificity and the cytopathic potential of HIV-2, with indistinguishable rules compared with HIV-1. Moreover, HIV-2 strains are not characterized by an intrinsically lower cytopathicity than HIV-1 strains. Therefore, direct cytopathic potential per se does not explain the unique behavior of HIV-2 in people, highlighting that other unknown factors need to be elucidated as the basis for their lesser virulence in vivo.

Reversal of Human Immunodeficiency Virus Type 1-Associated Hematosuppression by Effective Antiretroviral Therapy

Abstract: The immunodeficiency of human immunodeficiency virus type 1 (HIV-1) disease may be due to accelerated destruction of mature CD4+ T cells and/or impaired differentiation of progenitors of CD4+ T cells. HIV-1 infection may also inhibit the production of other hematopoietic lineages, by directly or indirectly suppressing the maturation of multilineage and/or lineage-restricted hematopoietic progenitor cells. To test this hypothesis, the effects of durable viral suppression on multilineage hematopoiesis in 66 HIV-1-seropositive patients were evaluated. Administration of effective antiretroviral therapy resulted in an increase in circulating CD4+ T cell counts and statistically significant increases in circulating levels of other hematopoietic lineages, including total white blood cells, lymphocytes, polymorphonuclear leukocytes, and platelets. These results suggest that a significant lesion in untreated HIV-1 disease may lie at the level of cell production from hematopoietic progenitors.

Impact of the Ovulatory Cycle on Virologic and Immunologic Markers in HIV-Infected Women

Abstract: An individual's sex influences plasma human immunodeficiency virus type 1 (HIV-1) RNA level and rate of CD4 cell decline, but the mechanism for this effect is currently unknown. To determine the effect of the ovulatory cycle on HIV-1 RNA level and lymphocyte subsets in HIV-infected women, blood specimens were obtained weekly from 14 women infected with HIV. Participants reported regular menses and were not using hormonal medications or narcotics. The occurrence of ovulation was verified by use of endocrine criteria. Ovulation occurred in 10 of the 14 women. Among women who ovulated, median HIV-1 RNA level fell by a median of 0.16 log10 from the early follicular phase to the midluteal phase (P=.03, Wilcoxon signed-rank test). When women who did not ovulate were included in the analysis, no significant fluctuation in plasma HIV RNA level was identified. Thus, the ovulatory cycle influenced circulating HIV-1 RNA levels, a finding that is plausible because of the known effect of sex hormones on lymphocyte function and cytokine production.

Loss of antiretroviral drug susceptibility at low viral load during early virological failure in treatment-experienced patients.

Abstract: Background: Clinical studies have demonstrated a correlation between the response to second-line antiretroviral therapy and the number of drugs in the regimen to which the virus is susceptible. These studies have largely been performed in patients with viral loads over 1000 copies/ml. Objectives: To examine the evolution of resistance during early virological failure, and the potential role of susceptibility testing in patients with low viral loads (below 1000 copies/ml), in treatment-experienced patients. Methods: Drug susceptibility and genotypes of HIV-1 from indinavir-experienced patients undergoing therapy with nelfinavir, saquinavir, abacavir and either a second nucleoside reverse transcriptase inhibitor (NRTI) or nevirapine were determined. Results: Sixteen subjects were studied. Five of the ten subjects treated with nevirapine, and one of six treated with a second NRTI, achieved and maintained plasma HIV RNA , 500 copies/ml. Virus from the treatment failures lost susceptibility to one or more treatment drugs, including nelfinavir and/or saquinavir, after 4 to 36 weeks of treatment. In six of the ten failures, virus with new reductions in drug susceptibility was detected prior to failure. In five of the six failures who had at least one plasma sample with a viral load between 50 and 1000 copies/ml, reductions in susceptibility to one or more treatment drugs were detected (viral load range: 260 to 630 copies/ml). Conclusions: Drug resistance can be detected at viral loads below 1000 copies/ml which may be predictive of treatment failure. Failure of a second line regimen was typically associated with early evolution of resistance in HIV protease.