Cell-Associated Simian Immunodeficiency Virus Accelerates Initial Virus Spread and CD4+ T-Cell Depletion in the Intestinal Mucosa

ABSTRACT The live, attenuated vaccine simian immunodeficiency virus SIVmac239Δnef efficiently protects rhesus macaques against infection with wild-type SIVmac but occasionally causes CD4+ T-cell depletion and progression to simian AIDS (SAIDS). Virus recovered from a vaccinated macaque (Rh1490) that progressed to SAIDS had acquired an additional deletion in the nef gene, resulting in a frameshift that restored the original nef open reading frame (R. I. Connor, D. C. Montefiori, J. M. Binley, J. P. Moore, S. Bonhoeffer, A. Gettie, E. A. Fenamore, K. E. Sheridan, D. D. Ho, P. J. Dailey, and P. A. Marx, J. Virol. 72:7501-7509, 1998). Intravenous inoculation of the Rh1490 viral isolate into four naive rhesus macaques induced CD4+ T-cell depletion and disease in three out of four animals within 2 years, indicating a restoration of virulence. A DNA fragment encompassing the truncated nef gene amplified from the Rh1490 isolate was inserted into the genetic backbone of SIVmac239. The resulting clone, SIVmac239-Δ2nef, expressed a Nef protein of approximately 23 kDa, while the original SIVmac239Δnef clone expressed a shorter protein of 8 kDa. The revertant form of Nef did not cause downregulation of CD4, CD3, or major histocompatibility complex class I. The infectivity of SIVmac239-Δ2nef was similar to that of SIVmac239Δnef in single-cycle assays using indicator cell lines. In contrast, SIVmac239-Δ2nef replicated more efficiently than SIVmac239Δnef in peripheral blood mononuclear cell (PBMC) cultures infected under unstimulated conditions. The p27 Gag antigen levels in SIVmac239-Δ2nef-infected cultures were still lower than those obtained with wild-type SIVmac239, consistent with a partial recovery of Nef function. The transcriptional activity of long terminal repeat (LTR)-luciferase constructs containing the nef deletions did not differ markedly from that of wild-type LTR. Introduction of a premature stop codon within Nef-Δ2 abolished the replicative advantage in PBMCs, demonstrating that the Nef-Δ2 protein, rather than the structure of the U3 region of the LTR, was responsible for the increase in viral replication. Taken together, these results show that SIV with a deletion in the nef gene can revert to virulence and that expression of a form of nef with multiple deletions may contribute to this process by increasing viral replication.

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The Majority of CD4+ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

Journal of Virology ◽

10.1128/jvi.03428-13 ◽

2014 ◽

Vol 88 (6) ◽

pp. 3202-3212 ◽

Cited By ~ 19

Author(s):

L. Matrajt ◽

P. M. Younan ◽

H.-P. Kiem ◽

J. T. Schiffer

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Cd4 T Cell ◽

Cell Depletion ◽

T Cell Depletion ◽

Immunodeficiency Virus

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Expanded Tissue Targets for Foamy Virus Replication with Simian Immunodeficiency Virus-Induced Immunosuppression

Journal of Virology ◽

10.1128/jvi.80.2.663-670.2006 ◽

2006 ◽

Vol 80 (2) ◽

pp. 663-670 ◽

Cited By ~ 57

Author(s):

S. M. Murray ◽

L. J. Picker ◽

M. K. Axthelm ◽

M. L. Linial

Keyword(s):

Small Intestine ◽

T Cell ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Foamy Virus ◽

Viral Rna ◽

Cell Depletion ◽

T Cell Depletion ◽

Immunodeficiency Virus

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.

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Intestinal Intraepithelial Lymphocytes Are Primed for Gamma Interferon and MIP-1β Expression and Display Antiviral Cytotoxic Activity despite Severe CD4+ T-Cell Depletion in Primary Simian Immunodeficiency Virus Infection

Journal of Virology ◽

10.1128/jvi.72.8.6421-6429.1998 ◽

1998 ◽

Vol 72 (8) ◽

pp. 6421-6429 ◽

Cited By ~ 76

Author(s):

Joseph J. Mattapallil ◽

Zeljka Smit-McBride ◽

Michael McChesney ◽

Satya Dandekar

Keyword(s):

T Cells ◽

T Cell ◽

Simian Immunodeficiency Virus ◽

Intraepithelial Lymphocytes ◽

Cell Depletion ◽

T Cell Depletion ◽

Immunodeficiency Virus ◽

Siv Infection ◽

Ifn Γ ◽

Ctl Activity

ABSTRACT Intraepithelial lymphocytes (IEL) are a critical effector component of the gut-associated lymphoid tissue (GALT) and play an important role in mucosal immunity as well as in the maintenance of the epithelial cell integrity and barrier function. The objective of this study was to determine whether simian immunodeficiency virus (SIV) infection of rhesus macaques would cause alterations in the immunophenotypic profiles of IEL and their mitogen-specific cytokine (gamma interferon [IFN-γ] and MIP-1β) responses (by flow cytometry) and virus-specific cytotoxic T-cell (CTL) activity (by the chromium release assay). Virally infected IEL were detected through the entire course of SIV infection by in situ hybridization. Severe depletion of CD4+ single-positive and CD4+CD8+ double-positive T cells occurred early in primary SIV infection, which was coincident with an increased prevalence of CD8+ T cells. This was in contrast to a gradual depletion of CD4+ T cells in peripheral blood. The CD8+ IEL were the primary producers of IFN-γ and MIP-1β and were found to retain their potential to produce both IFN-γ and MIP-1β through the entire course of SIV infection. SIV-specific CTL activity was detected in primary IEL at 1, 2, and 4 weeks post-SIV infection. These results demonstrated that IEL may be involved in generating antiviral immune responses early in SIV infection and in suppressing viral infection thereafter. Alterations in homeostasis in epithelia due to severe CD4+ T-cell depletion accompanied by changes in the cytokine and chemokine production by IEL may play a role in the enteropathogenesis of SIV infection.

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Identifying the Target Cell in Primary Simian Immunodeficiency Virus (SIV) Infection: Highly Activated Memory CD4+ T Cells Are Rapidly Eliminated in Early SIV Infection In Vivo

Journal of Virology ◽

10.1128/jvi.74.1.57-64.2000 ◽

2000 ◽

Vol 74 (1) ◽

pp. 57-64 ◽

Cited By ~ 190

Author(s):

Ronald S. Veazey ◽

Irene C. Tham ◽

Keith G. Mansfield ◽

MaryAnn DeMaria ◽

Amy E. Forand ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Simian Immunodeficiency Virus ◽

Cell Depletion ◽

Cell Type ◽

T Cell Depletion ◽

Cell Counts ◽

Immunodeficiency Virus ◽

Siv Infection

ABSTRACT It has recently been shown that rapid and profound CD4+T-cell depletion occurs almost exclusively within the intestinal tract of simian immunodeficiency virus (SIV)-infected macaques within days of infection. Here we demonstrate (by three- and four-color flow cytometry) that this depletion is specific to a definable subset of CD4+ T cells, namely, those having both a highly and/or acutely activated (CD69+ CD38+HLA-DR+) and memory (CD45RA−Leu8−) phenotype. Moreover, we demonstrate that this subset of helper T cells is found primarily within the intestinal lamina propria. Viral tropism for this particular cell type (which has been previously suggested by various studies in vitro) could explain why profound CD4+ T-cell depletion occurs in the intestine and not in peripheral lymphoid tissues in early SIV infection. Furthermore, we demonstrate that an acute loss of this specific subset of activated memory CD4+ T cells may also be detected in peripheral blood and lymph nodes in early SIV infection. However, since this particular cell type is present in such small numbers in circulation, its loss does not significantly affect total CD4+ T cell counts. This finding suggests that SIV and, presumably, human immunodeficiency virus specifically infect, replicate in, and eliminate definable subsets of CD4+ T cells in vivo.

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Simian immunodeficiency virus types 1 and 2 (SIV mnd 1 and 2) have different pathogenic potentials in rhesus macaques upon experimental cross-species transmission

Journal of General Virology ◽

10.1099/vir.0.005181-0 ◽

2009 ◽

Vol 90 (2) ◽

pp. 488-499 ◽

Cited By ~ 13

Author(s):

Sandrine Souquière ◽

Richard Onanga ◽

Maria Makuwa ◽

Ivona Pandrea ◽

Paul Ngari ◽

...

Keyword(s):

T Cell ◽

Simian Immunodeficiency Virus ◽

Virus Replication ◽

Rhesus Macaques ◽

Natural Infection ◽

Cell Depletion ◽

T Cell Depletion ◽

Viral Loads ◽

Cell Counts ◽

Immunodeficiency Virus

The mandrill (Mandrillus sphinx) is naturally infected by two types of simian immunodeficiency virus (SIV): SIVmnd types 1 and 2. Both of these viruses cause long-term, non-progressive infections in their natural host despite high plasma viral loads. This study assessed the susceptibility of rhesus macaques to infection by these two types of SIVmnd and compared the virological and basic immunological characteristics of the resulting infections with those observed in natural infection in mandrills. Whilst both SIVmnd types induced similar levels of virus replication during acute infection in both mandrills and macaques, they produced a more pronounced CD4+ T-cell depletion in rhesus macaques that persisted longer during the initial stage of infection. Pro-inflammatory cytokine responses were also induced at higher levels in rhesus macaques early in the infection. During the chronic phase of infection in mandrills, which in this case was followed for up to 2 years after infection, high levels of chronic virus replication did not induce significant changes in CD4+ or CD8+ T-cell counts. In rhesus macaques, the overall chronic virus replication level was lower than in mandrills. At the end of the follow-up period, although the viral loads of SIVmnd-1 and SIVmnd-2 were relatively similar in rhesus macaques, only SIVmnd-1-infected rhesus macaques showed significant CD4+ T-cell depletion, in the context of higher levels of CD4+ and CD8+ T-cell activation, compared with SIVmnd-infected mandrills. The demonstration of the ability of both SIVmnd types to induce persistent infections in rhesus macaques calls for a careful assessment of the potential of these two viruses to emerge as new human pathogens.

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