Muhammad Shahabuddin

Regulated Expression of Human Immunodeficiency Virus Type 1 in Human Glial Cells: Induction of Dormant Virus

Human neural cells are susceptible to infection with human immunodeficiency virus type 1 (HIV-1) in vitro; however, virus replication in these cells is strongly restricted. To understand the mechanism of this restriction, we examined the regulation of HIV-1 expression in glial cell cultures expressing high levels of HIV-1 after transfection of infectious viral DNA and selection. In all cases, high HIV-1 expression declined to low basal levels within 4-8 weeks of cultivation. The decrease in HIV-1 protein production wa paralleled by the decline in the relative levels of the 9.2-, 4.3- and 1.8-kilobase HIV-1 transcripts, but not by significant loss of HIV-1 DNA. Analysis of one long-term cell culture revealed 5 full-length unrearranged HIV-1 DNA copies per cell, but no viral transcripts on Northern blots, and minimal production of infectious virus. HIV-1 replication in these cells was markedly augmented by treatment with sodium butyrate (Na But) and to a lesser extent by 5-azacytidine, dibutyryl AMP and human herpes virus type 6. The virus induced by Na But was infectious. Transient expression assays revealed that Na But was more effective than phorbol myristate acetate in increasing the HIV-1 promoter activity in glial cells. Thus, one phase where glial cells can limit HIV infection is the expression of viral RNA from stable HIV provirus. However, such provirus remains responsive to inductive signals and may be activated to produce infectious HIV.

Uniform detection of HIV-1 in alveolar macrophages of pediatric but not adult AIDS patients.

Manifestations of pulmonary disease in pediatric AIDS patients differ from those in adults. To evaluate whether differences in the frequency of alveolar macrophage (AM) infection with human immunodeficiency virus type 1 (HIV‐1) could account for these clinical distinctions, we undertook a comparative analysis of HIV‐1 DNA in AMs from pediatric and adult AIDS patients by enzymatic amplification. A higher frequency of viral DNA detection in pediatric cases (100%) compared with adults (67%) was observed. The sensitivity of detection was 1 viral DNA copy per 4000 AMs; matched peripheral blood mononuclear cells from six of seven pediatric and eight of nine adult patients tested HIV‐1 DNA positive. Adult but not pediatric patients exhibited a marked alveolar lymphocytosis, 32% mean lymphocyte count compared with 7.0%, respectively. These results suggest that the burden of HIV‐1 in the lungs of pediatric AIDS patients is greater than that in adults.

The human immunodeficiency virus type 1 vif gene: the road from an accessory to an essential role in human immunodeficiency virus type 1 replication.

The vif (virion infectivity factor) gene is one of nine genes known to be expressed by human immunodeficiency virus (HIV)-1 (Wong-Staal and Gallo 1985; Haseltine 1988); vif and four other genes encode protein which are not structural components of virions but regulate viral replication to varying degrees (Haseltine 1988; Levy 1993). The two best-known viral regulatory genes, tat and rev, are essential for HIV-1 replication (Rosen et al. 1986; Sodroski et al. 1986b); in contrast, vif has been defined as an accessory gene because in initial studies its function was found to be dispensable for virus infection of transformed T cell lines (Sodroski et al. 1986a; Fisher et al. 1987; Strebel et al. 1987). After the initial description of vif and the effects of its ablation on virus replication (Sodroski et al. 1986a; Fisher et al. 1987; Strebel et al. 1987), very little research was done to further the understanding of the function of this viral gene product. Recently, however, a number of laboratories made the unexpected observation that vif is required for HIV-1 infection in its primary target cells, CD4-bearing T lymphocytes (Akari et al. 1992; Fan and Peden 1992; Gabuzda et al. 1992; Michaels et al. 1993; von Schwedler et al. 1993). This all-or-none dependence on the expression of vif for HIV-1 infection of peripheral blood lymphocytes (PBL) is illustrated in Fig. 1. These findings mandate the redefinition of vif as an essential gene for HIV-1 replication. We shall review the studies on the role of vif in HIV-1 infection and shall attempt to incorporate the results from different systems in the construction of a testable model for the mechanism of action of Vif. Because the cell-type dependence of Vif activity has become apparent only recently, early studies must be interpreted with these new variables in mind.

The Role of Human Immunodeficiency Virus Type 1 (HIV-1) in Neurologic Disorders of AIDS

As the second decade of the AIDS pandemic begins, many aspects of this multifaceted syndrome become familiar. The principal etiologic agent of AIDS has been identified as a novel member of lentiviruses, human immunodeficiency virus type 1 (HIV-1). The genetic structure of HIV-1, its life cycle, and many of its functions have been elucidated in some detail. The major routes of HIV-1 infection, spread, and principal target tissues have been determined. Progress has been made in correlating the known effects of HIV-1 infection in vitro, the abnormalities observed in HIV-1 infected persons, and predicted function(s) of HIV-1 infection in AIDS pathogenesis. Antiviral and immuno-regulatory drugs have been developed to counter specific effects of the virus. AIDS patients live longer and have a better quality of life. Several brief reviews of these developments are included in a special issue of the FASEB Journal “AIDS: Ten years later” (1), many more comprehensive reviews appeared in the past (2, 3, 4, 5). The flowchart shown in Fig. 1 summarizes the current state of knowledge regarding the pathogenesis of AIDS as a retrovirally-induced disease.