Expanded tissue targets for foamy virus replication with simian immunodeficiency virus-induced immunosuppression

Abstract

Foamy viruses (FV) are the oldest known genus of retroviruses and have persisted in nonhuman primates for over 60 million years. FV are efficiently transmitted, leading to a lifelong nonpathogenic infection. Transmission is thought to occur through saliva, but the detailed mechanism is unknown. Interestingly, this persistent infection contrasts with the rapid cytopathicity caused by FV in vitro, suggesting a host defense against FV. To better understand the tissue specificity of FV replication and host immunologic defense against FV cytopathicity, we quantified FV in tissues of healthy rhesus macaques (RM) and those severely immunosuppressed by simian immunodeficiency virus (SIV). Contrary to earlier findings, we find that all immunocompetent animals consistently have high levels of viral RNA in oral tissues but not in other tissues examined, including the small intestine. Strikingly, abundant viral transcripts were detected in the small intestine of all of the SIV-infected RM, which has been shown to be a major site of SIV (and human immunodeficiency virus)-induced CD4+ T-cell depletion. In contrast, there was a trend to lower viral RNA levels in oropharyngeal tissues of SIV-infected animals. The expansion of FV replication to the small intestine but not to other CD4+ T-cell-depleted tissues suggests that factors other than T-cell depletion, such as dysregulation of the jejunal microenvironment after SIV infection, likely account for the expanded tissue tropism of FV replication.

FIG. 1.

Foamy virus DNA loads in peripheral blood mononuclear cells of SIV⁻ and SIV⁺ RM. Each symbol indicates the mean normalized SFV DNA level from two independent assays run in duplicate from an individual animal. The lower limit of detection of the assay is shown by the dotted line. All animals which were negative by ELISA had DNA levels below the level of detection.

FIG. 2.

Foamy virus RNA loads in the oral cavity of SIV⁻ and SIV⁺ RM. RNA levels from buccal swabs were normalized to cell equivalents using a qRT-PCR for 18S RNA. Each symbol indicates the SFV RNA mean value from two independent assays, each run in duplicate from an individual animal. The lower limit of detection of the assay is shown by the dotted line. All animals which were negative by ELISA had RNA levels below the level of detection.

FIG. 3.

Foamy virus RNA levels in permissive tissues of healthy RM. Results of qRT-PCR for SFV RNA in tissues from five SIV⁻ RM are shown. Each bar represents the mean viral load from three independent qRT-PCRs for one animal. Viral loads were normalized to cell equivalents by qRT-PCR for 18S RNA. Error bars represent the standard deviations. All SFV-seronegative RM were PCR negative for SFV RNA in all tissues examined. ND, not determined. *, undetectable.

FIG. 4.

Foamy virus RNA levels in permissive oropharyngeal tissues of SIV-immunosuppressed RM. Results of qRT-PCR for SFV RNA in tissues from four SIV⁺ immunosuppressed RM are shown. Analysis was done as in Fig. 3. Error bars represent the standard deviations. All SFV-seronegative RM were PCR negative for SFV RNA in all tissues examined. ND, not determined. *, undetectable.

FIG. 5.

Foamy virus replication is expanded to the small intestine of SIV-immunosuppressed RM. Results of qRT-PCR for SFV⁺ and SFV⁻ RNA are shown. Each bar represents the mean viral load from three independent qRT-PCRs for one animal. Viral loads were normalized to cell equivalents by a qRT-PCR for 18S RNA. Error bars represent the standard deviations. *, undetectable.