Variation in the Biological Properties of HIV-1 R5 Envelopes: Implications of Envelope Structure, Transmission and Pathogenesis

Abstract

HIV-1 R5 viruses predominantly use CCR5 as a coreceptor to infect CD4 + T cells and macrophages. While R5 viruses generally infect CD4 + T cells, research over the past few years has demonstrated that they vary extensively in their capacity to infect macrophages. Thus, R5 variants that are highly macrophage tropic have been detected in late disease and are prominent in brain tissue of subjects with neurological complications. Other R5 variants that are less sensitive to CCR5 antagonists and use CCR5 differently have also been identified in late disease. These latter variants have faster replication kinetics and may contribute to CD4 T-cell depletion. In addition, R5 viruses are highly variable in many other properties, including sensitivity to neutralizing antibodies and inhibitors that block HIV-1 entry into cells. Here, we review what is currently known about how HIV-1 R5 viruses vary in cell tropism and other properties, and discuss the implications of this variation on transmission, pathogenesis, therapy and vaccines. Keywords CCR5; CD4; CD4 + T cell; envelope; HIV-1; macrophage; macrophage tropism; neuroAIDS; R5; receptor; tropism HIV-1 was first described in 1983 [1] and CD4 identified as its receptor in 1984 [2,3]. It was quickly apparent that CD4 alone was not sufficient for infection and that a putative second determinant was required for HIV-1 entry. The identification of CXCR4 in 1996 by Ed Berger's group as the coreceptor for T-tropic HIV-1 strains [4] thus heralded a new era for HIV-1 receptor and cell tropism research. Well before 1996, it was clear that there were two types of HIV-1 that infected primary T cells or macrophages with different efficiencies. The first type

A Conserved Determinant in the V1 Loop of HIV-1 Modulates the V3 Loop To Prime Low CD4 Use and Macrophage Infection

“…The CD4 binding loop is likely to be the main part of the CD4bs that is exposed on the native envelope trimer and an early contact for CD4 (7). Of note, the identified CD4 binding loop flank residues also shifted sensitivity to the glycan-specific monoclonal antibody (MAb), 2G12, indicating that movement of proximal glycans could be one mechanism involved in the exposure of CD4 contact residues (12).…”

Human Immunodeficiency Virus Infects Human Seminal Vesicles in Vitro and in Vivo

“…Therefore, X4 strains are selected against both during transmission and over the course of the disease by a range of potential mechanisms. 37 Although X4 variants can sometimes be detected in semen, R5 viruses seem to predominate (reviewed by Duenas-Decamp et al 38 ), which may reflect selective replication in the male genital tract organs. Whether the restriction for CXCR4-using variants occurs in the seminal vesicles and prostate gland in vivo remains to be determined.…”

“…41,42 Therefore, it cannot be excluded that a subset of X4 strains may be able to replicate in the seminal vesicle resident macrophages. Furthermore, although HIV-1 R5 SF162 behaves similarly to primary macrophage-tropic R5 strains, 43 not all CCR5-using strains are macrophage-tropic (reviewed by Duenas-Decamp et al 38 ). Our observation of HIV infection of the seminal vesicles in vitro was confirmed in vivo via analysis of the seminal vesicle tissues from nine HIV-infected men.…”

Tropism and Properties of the HIV-1 Envelope Glycoprotein in Transmission

“…R5 viruses are generally able to infect CD4+ T-cells. However, they vary extensively in macrophage infection, with highly mac-tropic variants present in the brain and non-mac-tropic R5 viruses predominant in immune tissue (Duenas-Decamp et al 2010). CXCR4-using variants do target CD4+ T-cells when they emerge.…”

“…Macrophages express much lower amounts of CD4 compared to T-cells. An important determinant of macrophage infectivity for R5 viruses is an Env adaptation to use these low amounts of CD4 on the cell surface for infection (Duenas-Decamp et al 2010). Current data suggest that successfully transmitting viruses are predominantly non-mac-tropic R5, although little is known about the factors during transmission that confer this selection.…”