Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population

Abstract

The composition of human immunodeficiency virus type 1 (HIV-1) clonal populations at different stages of infection and in different compartments was analyzed. Biological HIV-1 clones were obtained by primary isolation from patient peripheral blood mononuclear cells under limiting dilution conditions, with either blood donor peripheral blood lymphocytes or monocyte-derived macrophages (MDM) as target cells, and the biological phenotype of the clones was analyzed. In asymptomatic individuals, low frequencies of HIV-1 clones were observed. These clones were non-syncytium inducing and preferentially monocytotropic. In individuals progressing to disease, a 100-fold increase in frequencies of productively HIV-1-infected cells was observed as a result of a selective expansion of nonmonocytotropic clones. In a person progressing to AIDS within 19 months after infection, only syncytium-inducing clones were detected, shifting from MDM-tropic to non-MDMtropic over time. From his virus donor, a patient with wasting syndrome, only syncytium-inducing clones, mostly non-MDM-tropic, were recovered. Parallel clonal analysis of HIV-1 populations in cells present in bronchoalveolar lavage fluid and peripheral blood from an AIDS patient revealed a qualitatively and quantitatively more monocytotropic virus population in the lung compartment than in peripheral blood at the same time point. These findings indicate that monocytotropic HIV-1 clones, probably generated in the tissues, are responsible for the persistence of HIV-1 infection and that progression of HIV-1 infection is associated with a selective increase of T-cell-tropic, nonmonocytotropic HIV-1 variants in peripheral blood.

HIV: Cell Binding and Entry

“…With rare exception, only R5 and R5X4 viruses are transmitted between individuals (Keele et al 2008), likely owing to multiple imperfect but overlapping host restrictions on X4 HIV transmission (reviewed in Margolis and Shattock 2006). Interestingly, despite identification at earlier time points and despite high levels of CXCR4 expression on circulating HIV target cells, X4 or even R5X4 HIV rarely predominate until late in infection (Tersmette et al 1989;Schuitemaker et al 1992;Connor et al 1997). In addition, X4 viruses are less common in clade C HIVand SIV infection (Chen et al 1998;Ping et al 1999;Cecilia et al 2000;Huang et al 2007 Overview of HIV entry.…”

Molecular determinants of human immunodeficiency virus type I phenotype variability

“…This suggests that in the course of infection increased T-cell tropism is not restricted to SI isolates but also a subpopulation of NSI variants may gradually gain an increased capacity to replicate in T cells. These observations may at least in part explain the increased virus load in late asymptomatic HIV infection in individuals, regardless of SI capacity of the variants present in the infected individuals [13,140,141]. Since V3 together with other variable domains determine both SI capacity and tropism of HIV-1, evolution from NSI macrophage-tropic towards SI and/or T-cell-tropic isolates may result from consecutive changes in these variable domains [65,66,68,70,71,[92][93][94]100,104].…”

“…Whereas in the early asymptomatic stage of infection macrophage-tropic isolates represent the major virus population in HIV-infected individuals, in the course of infection the majority of virus isolates have limited macrophage-tropic capacity but display increased tropism for CD4-positive T cells ( Fig. 3) [13,18]. This suggests that upon establishment of persistent infection with HIV-1 in vivo, T-cell tropic capacity of HIV-1 is advantageous compared with macrophage tropic capacity.…”

“…HIV-1 isolates obtained from infected individuals in the early asymptomatic stage of infection generally display low replication rates, lack syncytium-inducing (SI) capacity and replicate efficiently in macrophages but not in transformed T-cell lines [11][12][13]. In progressive stages of HIV-1 infection the majority of virus variants present in infected individuals display increased replication rates, decreased capacity to replicate in macrophages but increased T-cell tropism [11][12][13][14][15] and in about 50% of infected individuals gain SI capacity [16,17]. This correlation between HIV-1 phenotype and the stage of infection suggests that HIV-1 phenotype variability plays an important role in the pathogenesis of AIDS.…”

Evidence for a role of T‐helper type 2 cytokines in the acquisition of human immunodeficiency virus syncytium‐inducing phenotype

“…Based on these traits, HIV-1 variants are classified as non-syncytiuminducing (NSI), mostly low-replicating strains, and highreplicating syncytium-inducing (SI) variants [2][3][4]. The appearance of SI strains during the chronic phase of HIV-1 infection is associated with an increased rate of CD4 þ cell decline and a more aggressive course of the disease [4][5][6][7][8][9][10][11][12]. Clearly, the host immune response to HIV also affects the progress of the infection.…”