APOBEC3A is a specific inhibitor of the early phases of HIV-1 infection in myeloid cells.

Myeloid cells play numerous roles in HIV-1 pathogenesis serving as a vehicle for viral spread and as a viral reservoir. Yet, cells of this lineage generally resist HIV-1 infection when compared to cells of other lineages, a phenomenon particularly acute during the early phases of infection. Here, we explore the role of APOBEC3A on these steps. APOBEC3A is a member of the APOBEC3 family that is highly expressed in myeloid cells, but so far lacks a known antiviral effect against retroviruses. Using ectopic expression of APOBEC3A in established cell lines and specific silencing in primary macrophages and dendritic cells, we demonstrate that the pool of APOBEC3A in target cells inhibits the early phases of HIV-1 infection and the spread of replication-competent R5-tropic HIV-1, specifically in cells of myeloid origins. In these cells, APOBEC3A affects the amount of vDNA synthesized over the course of infection. The susceptibility to the antiviral effect of APOBEC3A is conserved among primate lentiviruses, although the viral protein Vpx coded by members of the SIV(SM)/HIV-2 lineage provides partial protection from APOBEC3A during infection. Our results indicate that APOBEC3A is a previously unrecognized antiviral factor that targets primate lentiviruses specifically in myeloid cells and that acts during the early phases of infection directly in target cells. The findings presented here open up new venues on the role of APOBEC3A during HIV infection and pathogenesis, on the role of the cellular context in the regulation of the antiviral activities of members of the APOBEC3 family and more generally on the natural functions of APOBEC3A.

Robust suppression of env-SHIV viremia in Macaca nemestrina by 3-drug ART is independent of timing of initiation during chronic infection.

BACKGROUND: Nonhuman primates (NHPs) are an important model organism for studies of HIV pathogenesis and preclinical evaluation of anti-HIV therapies. The successful translation of NHP-derived data to clinically relevant anti-HIV studies will require better understanding of the viral strains and NHP species used and their responses to existing antiretroviral therapies (ART). METHODS: Five pigtailed macaques (Macaca nemestrina) were productively infected with the SIV/HIV chimeric virus SHIV-1157 ipd3N4 following intravenous challenge. After 8 or 27 weeks, ART (PMPA, FTC, raltegravir) was initiated. Viral load, T-cell counts, and production of SHIV-specific antibodies were monitored throughout the course of infection and ART. RESULTS: ART led to a rapid and sustained decrease in plasma viral load. Suppression of plasma viremia by ART was independent of the timing of initiation during chronic infection. CONCLUSIONS: We present a new NHP model of HIV infection on antiretroviral therapy, which should prove applicable to multiple clinically relevant anti-HIV approaches.

A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge.

The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. The "closed," antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.

Inhibition of HIV-1, HIV-2 and SIV envelope glycoprotein-mediated cell fusion by calmodulin.

Calmodulin, an EF-hand protein, inhibited the fusion between CD4+ human cells and cells stably expressing HIV-1 envelope proteins. Fusion was also inhibited when HIV-1, HIV-2 or SIV envelope glycoproteins were expressed by vaccinia virus (VV) recombinants, but calmodulin did not inhibit syncytia formation induced by measles virus glycoproteins. Calmodulin also inhibited fusion induced by vPE17, a VV-recombinant expressing a truncated form of HIV-1gp160 which lacks the two known calmodulin-binding sites located in the cytoplasmic domain of gp41. The inhibitory activity was specific to calmodulin among the EF-hand proteins. These observations may be important in understanding the mechanism of retroviral envelope glycoprotein-mediated cell fusion. Several possible mechanisms of action are discussed.