HIV envelope induces a cascade of cell signals in non-proliferating target cells that favor virus replication

Abstract

Certain HIV-encoded proteins modify host-cell gene expression in a manner that facilitates viral replication. These activities may contribute to low-level viral replication in nonproliferating cells. Through the use of oligonucleotide microarrays and high-throughput Western blotting we demonstrate that one of these proteins, gp120, induces the expression of cytokines, chemokines, kinases, and transcription factors associated with antigen-specific T cell activation in the absence of cellular proliferation. Examination of transcriptional changes induced by gp120 in freshly isolated peripheral blood mononuclear cells and monocyte-derivedmacrophages reveals a broad and complex transcriptional program conducive to productive infection with HIV. Observations include the induction of nuclear factor of activated T cells, components of the RNA polymerase II complex including TFII D, proteins localized to the plasma membrane, including several syntaxins, and members of the Rho protein family, including Cdc 42. These observations provide evidence that envelope-mediated signaling contributes to the productive infection of HIV in suboptimally activated T cells.H IV preferentially replicates in proliferating CD4 ϩ T cells(1). However recent evidence suggests that, in vivo, resting and suboptimally activated T cells may serve as targets for low-level productive infection in the absence of cellular proliferation (2-5). Infection in this manner may contribute to the establishment and͞or maintenance of persistent viral reservoirs that currently prevent the eradication of virus. To productively infect suboptimally activated CD4 ϩ T cells, HIV must overcome post-entry barriers to replication (6-8).DNA microarrays have been used to characterize the effect of HIV on target cell transcription (9, 10); in one microarray-based study, HIV Nef was shown to diminish barriers to viral replication by mimicking antigen-specific T cell proliferation signals (11,12). It has been suggested that HIV gp120 also facilitates replication in suboptimally activated cells (12-15). Gp120 transduces near-simultaneous signals through CD4 (16), a component of the T cell receptor complex, and CCR5, a chemokine receptor (17)(18)(19). In vivo concentrations of gp120 (20, 21) fall within the range required to induce signaling in vitro (17)(18)(19)22). To provide a more complete picture of the complex cascade of signals induced by gp120, we treated freshly isolated peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) with an envelope derived from a CCR5-using virus and measured temporal changes in the levels of mRNA by using Affymetrix (Santa Clara, CA) U95A oligonucleotide microarrays that include probes encompassing Ϸ12,600 genes. In addition, we used a high-throughput Western blot analysis that allowed us to screen protein lysates with 800 monoclonal antibodies. The gp120 used was derived from JR-FL, a CCR5-tropic molecular clone obtained from a minimally passaged viral isolate (23). We used concentrations of envelope near or bel...

Vav exchange factor counteracts the HIV‐1 Nef‐mediated decrease of plasma membrane GM1 and NF‐AT activity in T cells

“…Our data suggest that the presence of Nef in HIV-infected cells, although rendering these cells unable to express antigen-specific effector functions, ensure a level of cellular activation that favor HIV replication and the suppression of the immune surveillance. This evidence is in agreement with recent findings obtained by using gene expression profiling revealingthat the two HIV-encoded proteins Nef and gp120 promote kinases and transcription factors associated with antigen-specific T cell activation and viral replication [50,51]. Moreover, our evidence that Vav can circumvent the immunological defects by reconstituting all features of full T cell activation, suggests that a strategy to overcome the problem of viral reservoirs could associate highly active antiretroviral therapy (HAART) to cytoskeleton activators.…”

Long-Term Productive Human Immunodeficiency Virus Infection of CD1a-Sorted Myeloid Dendritic Cells

“…T cells upon contact with noninfected MDC undergo activation, which leads to the upregulation of HLA-DR, CD25, and CD69 (31). According to earlier data, activation of T cells is one of prerequisites for productive HIV replication (8,22,28). We found that even a low amount of HIV released by the long-term infected MDC was sufficient to rapidly spread infection in the MDC-T-cell microenvironment.…”

R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells

“…ϩ T cells to apoptose in vitro (12)(13)(14)(15). Envelope proteins have also been shown to disrupt antigen-specific CD4 ϩ T cell responses (16).…”

“…In vitro exposure of resting CD4 ϩ T cells derived from HIV-infected individuals to envelope results in a burst of viral replication (19). Insight into the mechanisms that produce this burst was obtained from a study of the gene expression profiles in peripheral blood mononuclear cells (PBMCs) treated with gp120 derived from an R5 strain of HIV (14). Envelope treatment induced the expression of multiple factors that promote viral replication.…”