Gene Expression Profiling of Host Response in Models of Acute HIV Infection

Abstract

HIV infection is characterized by a host response composed of adaptive and innate immunity that partially limits viral replication; however, it ultimately fails in eradicating the virus. To model host gene expression during acute HIV infection, we infected cynomolgus macaques with the SIV/HIV-1 chimeric virus, SHIV89.6P, and profiled gene expression in peripheral blood over a 5-wk period using a high density cDNA microarray. We demonstrate that viral challenge induced a widespread suppression of genes regulating innate immunity, including the LPS receptors, CD14 and TLR4. An overexpression of 16 IFN-stimulated genes was also observed in response to infection; however, it did not correlate with control over viral titers. A statistical analysis of the dataset identified 10 genes regulating apoptosis with differential expression during the first 2 wk of infection (p < 0.004). Quantitative real-time PCR verified transcriptional increases in IFN-␣-inducible genes and decreases in genes regulating innate immunity. Therefore, the persistence of high viral loads despite an extensive IFN response suggests that HIV can resist in vivo IFN treatment despite published reports of in vitro efficacy. The transcriptional suppression of genes regulating innate immunity may allow HIV to evade acute host responses and establish a chronic infection and may reduce innate host defense against opportunistic infections.

Anti-HIV State but Not Apoptosis Depends on IFN Signature in CD4+ T Cells

“…However, this antiviral response cannot fully control HIV replication. Our data are consistent with previous reports, demonstrating that the innate immunity does sense and respond to HIV, but is inefficient in constraining the virus (13,44,45). Molecular mechanisms permitting HIV to escape from the antiviral IFN response likely contribute to this failure of the innate immune system.…”

“…High-throughput gene expression profiling has also been performed on other cell types, such as monocyte-derived macrophages (7), monocyte-derived immature DCs (8), and peripheral blood from simian-HIV-infected macaques (13). In these systems, up-regulation of ISGs was also found.…”

“…Several in vitro and animal models of acute HIV infection have been used, including macrophages (7), monocyte-derived immature dendritic cells (DCs) (8), CD4 ϩ T cell lines (9 -11), and PBMCs (12)(13)(14). No information, however, is available on HIV-induced changes of host gene expression in primary CD4 ϩ T cells from lymphoid tissues.…”

To kill or be killed: how HIV exhausts the immune system

“…12 Gene expression profiling of macaques acutely infected with SIV/HIV-1 chimeric virus (SHIV) demonstrated a differential expression of 10 apoptosis regulators during the first 2 weeks of infection, including TNFRSF6 (tumor necrosis factor receptor superfamily, member 6 (FAS)), BCL2, BCL2L1, DAD1,TIAL1 and PDL2. 13 Accordingly, pathogenic SHIV was shown to induce an accumulation of apoptotic cells during the second week of infection in both lymph nodes and thymus, which colocalized to sites of both virus replication and CD4 T-cell loss. 14 …”

HIV-1 immunopathogenesis: How good interferon turns bad

“…Other in vivo reports indicated that elevated IFN-stimulated gene expression was associated with disease progression in HIV-infected patients following cessation of HAART (R A Lempicki et al, unpublished observations), as well as in SIV-infected cynomolgus macaques [19]. Type I interferon produced in lymphoid tissue (LT) of macaques infected with SIV did not inhibit viral replication [20].…”