Comparison of Viral Env Proteins from Acute and Chronic Infections with Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences in Glycosylation and CCR5 Utilization and Suggests a New Strategy for Immunogen Design

Abstract

Understanding human immunodeficiency virus type 1 (HIV-1) transmission is central to developing effective prevention strategies, including a vaccine. We compared phenotypic and genetic variation in HIV-1 env genes from subjects in acute/early infection and subjects with chronic infections in the context of subtype C heterosexual transmission. We found that the transmitted viruses all used CCR5 and required high levels of CD4 to infect target cells, suggesting selection for replication in T cells and not macrophages after transmission. In addition, the transmitted viruses were more likely to use a maraviroc-sensitive conformation of CCR5, perhaps identifying a feature of the target T cell. We confirmed an earlier observation that the transmitted viruses were, on average, modestly underglycosylated relative to the viruses from chronically infected subjects. This difference was most pronounced in comparing the viruses in acutely infected men to those in chronically infected women. These features of the transmitted virus point to selective pressures during the transmission event. We did not observe a consistent difference either in heterologous neutralization sensitivity or in sensitivity to soluble CD4 between the two groups, suggesting similar conformations between viruses from acute and chronic infection. However, the presence or absence of glycosylation sites had differential effects on neutralization sensitivity for different antibodies. We suggest that the occasional absence of glycosylation sites encoded in the conserved regions of env, further reduced in transmitted viruses, could expose specific surface structures on the protein as antibody targets.

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

“…In this context, it is critical to know whether transmitted viruses possess unique biological properties that predispose them to establish new infections more efficiently. This is a controversial topic, because some studies have reported TF-specific traits (22,24,26,52,(55)(56)(57), whereas others have failed to confirm these results (27,28,53,58,59). Some of these discrepancies are likely due to the fact that most previous analyses did not compare HIV-1 strains from transmission pairs.…”

“…in activated CD4 + T cells but not macrophages (14,(22)(23)(24)(25). Moreover, analysis of a comprehensive panel of infectious molecular clones (IMCs) showed that TF viruses packaged more envelope glycoprotein (Env), exhibited greater infectivity, bound to monocyte-derived dendritic cells more efficiently, and replicated to higher titers in CD4 + T cells in the presence of the type 1 interferon IFNα2 than chronic control (CC) viruses (26).…”

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

“…It has been argued that resting T cells may be involved in initial HIV-1 infections at mucosal sites, while infec-tion of activated T cells plays a far greater role during systemic dissemination and propagation of the virus (55). In a recent study, a substantial proportion of chronic viruses (but not transmitted/ founder viruses) were incompletely inhibited by a saturating concentration of MVC (56,57). This viral phenotype was most clearly seen in a cell line expressing very high levels of both CD4 and CCR5, but it was also detectable using primary CD4 ϩ T cells (56).…”

Phenotypic Correlates of HIV-1 Macrophage Tropism

“…Most M-tropic variants use the CCR5 coreceptor (R5 M-tropic), but X4 M-tropic viruses have been reported (16). Because M-tropic variants are detected so rarely (3,17), the true frequency and characteristics of M-tropic viruses are only beginning to be explored.…”

“…The vast majority of HIV-1 isolates sampled during acute and chronic infections are CCR5-using T cell-tropic (R5 T-tropic) viruses, which are adapted to (1)(2)(3), and replicating in (4-6), CD4 ϩ memory T cells. R5 T-tropic viruses require the high densities of the CD4 receptor found on CD4 ϩ T cells for efficient entry and use the CCR5 coreceptor, which is most abundant on the memory subset of CD4 ϩ T cells.…”