Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates

Abstract

Sequential human immunodeficiency virus (HIV) isolates, recovered from a panel of longitudinally collected peripheral blood mononuclear cells obtained from 20 initially asymptomatic HIV-seropositive homosexual men, were studied for differences in replication rate, syncytium-inducing capacity, and host range. Eleven individuals remained asymptomatic; nine progressed to acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) at the time point at which the last HIV isolate was obtained. In 16 individuals, only non-syncytium-inducing (NSI) isolates, with a host range restricted to mononuclear cells, were observed. From four individuals, high-replicating, syncytium-inducing (SI) isolates that could be transmitted to the H9, RC2A, and U937 cell lines were recovered. From two of these four individuals, SI isolates were obtained throughout the observation period. In the two others, a transition from NSI to SI HIV isolates was observed during the period of study. Three of these four individuals developed ARC or AIDS 9 to 15 months after the first isolation of an SI isolate. With the exception of the two individuals in whom a transition from NSI to SI isolates was observed, within a given individual the replication rate of sequential HIV isolates was constant. A significant correlation was found between the mean replication rate of isolates obtained from an individual and the rate of CD4+ cell decrease observed in this individual. In individuals with low-replicating HIV isolates, no significant CD4+ cell loss was observed. In contrast, recovery of high-replicating isolates, in particular when these were SI isolates, was associated with rapid decline of CD4+ cell numbers and development of ARC or AIDS. These findings indicate that variability in the biological properties of HIV isolates is one of the factors influencing the course of HIV infection.

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

“…Syncytia arise as a consequence of fusion between HIV-infected cells that express the viral envelope protein gp120 at the cell surface and cells that express the HIV receptor CD4. HIV-1 isolates may be classified on the basis of their ability to induce syncytia in peripheral blood mononuclear cells (PBMCs) or transformed T-cell lines as SI or non-syncytium inducing (NSI) [16].…”

“…Early in infection, the majority of HIV-infected individuals have exclusively NSI variants [16,18]. About 50% of HIV-1 infected individuals maintain exclusively NSI isolates, whereas in the other 50% SI isolates emerge in the course of infection [19].…”

“…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.…”