Restriction of HIV-1 (Subtype B) Replication at the Entry Step in Rhesus Macaque Cells

Abstract

Human immunodeficiency virus type 1 (HIV-1) is restricted for replication in rhesus macaque cells and does not establish infection in this species. The block to productive infection of macaque peripheral blood mononuclear cells (PBMC) in culture was investigated. A chimeric virus SHIV containing HIV-1 tat, rev, and env and all other genes from a simian immunodeficiency virus clone pathogenic in macaques (i.e., SIVmec239) replicated efficiently in macaque PBMC. Thus, the attachment step, involving interaction of the HIV-1 env glycoprotein with the cell surface CD4 receptor, is not blocked. Analysis of uptake of HIV-1 particles in these cells revealed a small reduction in virion entry; however, viral DNA synthesis, measured by PCR amplification, was greatly reduced. Taken together, these results indicate that the block to HIV-1 (subtype B) replication in rhesus macaque cells involves release of the virion core into the cytoplasm and/or a step immediately prior to initiation of reverse transcription. Further studies are required to characterize this block through identification of species-specific cellular proteins that interact with HIV-1 proteins in the early phase of viral replication.

Binding and Susceptibility to Postentry Restriction Factors in Monkey Cells Are Specified by Distinct Regions of the Human Immunodeficiency Virus Type 1 Capsid

“…For example, the diameter of the holes formed at the center of the hexameric rings (ϳ25 Å ) or between hexamers (ϳ107 Å ) could potentially accommodate soluble host factors that may perturb the ability of the CA core to uncoat (34). Such a model is consistent with the observation that the block to HIV-1 infection in monkey cells occurs at a step prior to reverse transcription (15,29,37).…”

“…Disassembly of the core must occur rapidly, as very little CA protein can be found associated with the reverse transcription complex (17). Uncoating events are likely to be relevant to HIV-1 tropism restrictions in cells of some nonhuman primate species, given the substantial reduction in reverse transcription products detected in newly infected cells (2,15,29). Thus, although HIV-1 entry into cells of several Old World monkey species is efficiently supported by simian CD4 and chemokine coreceptors (14,35), HIV-1 infection of these cells is restricted at a postentry step (2,3,15,28,31,45).…”

TRIM5α Cytoplasmic Bodies Are Highly Dynamic Structures

“…TRIM5␣-mediated restriction is saturable with high multiplicity of infection (MOI), and the specificity of TRIM5␣-mediated HIV-1 restriction is governed by the recognition of a capsid determinant in the restricted virus similar to the case of Fv1-mediated restriction of MLV infection (Towers et al, 2000;Cowan et al, 2002;Owens et al, 2003Owens et al, , 2004Hatziioannou et al, 2004). However, TRIM5␣-mediated restriction differs from Fv1-mediated restriction in that TRIM5␣-mediated restriction is manifested earlier in the infectious pathway, before the accumulation of reverse transcription products (Shibata et al, 1995;Himathongkham and Luciw, 1996;Cowan et al, 2002;Munk et al, 2002).…”

“…TRIM5␣-mediated restriction is saturable with high multiplicity of infection (MOI), and the specificity of TRIM5␣-mediated HIV-1 restriction is governed by the recognition of a capsid determinant in the restricted virus similar to the case of Fv1-mediated restriction of MLV infection (Towers et al, 2000;Cowan et al, 2002;Owens et al, 2003Owens et al, , 2004Hatziioannou et al, 2004). However, TRIM5␣-mediated restriction differs from Fv1-mediated restriction in that TRIM5␣-mediated restriction is manifested earlier in the infectious pathway, before the accumulation of reverse transcription products (Shibata et al, 1995;Himathongkham and Luciw, 1996;Cowan et al, 2002;Munk et al, 2002).Specifically, the TRIM5␣ proteins from rhesus monkey (rhTRIM5␣) and African green monkey (agmTRIM5␣) have been shown to restrict HIV-1 infection Yap et al, 2004;Song et al, 2005c). Additionally, rhTRIM5␣ and agmTRIM5␣ as well as the human variant of TRIM5␣ (huTRIM5␣) were subsequently identified as the factors responsible for restricting the infection by N-tropic MLV in cell lines derived from these species (Hatziioannou et al, 2004;Keckesova et al, 2004;Yap et al, 2004;Song et al, 2005c).…”

Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer

“…However, although Fv1 and huTRIM5␣ seem to interact with the retroviral capsid at an early postentry step, the mechanisms of restriction appear to differ. huTRIM5␣ usually acts before RT, whereas Fv1 allows RT but blocks subsequent steps, including integration into the host genome (2,7,12,21,36,37).…”