The Large Intestine as a Major Reservoir for Simian Immunodeficiency Virus in Macaques with Long-Term, Nonprogressing Infection

Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana 70433, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 11/2010; 202(12):1846-54. DOI: 10.1086/657413
Source: PubMed


Although patients with human immunodeficiency virus type 1 infection who are receiving antiretroviral therapy and those with long-term, nonprogressive infection (LTNPs) usually have undetectable viremia, virus persists in tissue reservoirs throughout infection. However, the distribution and magnitude of viral persistence and replication in tissues has not been adequately examined. Here, we used the simian immunodeficiency virus (SIV) macaque model to quantify and compare viral RNA and DNA in the small (jejunum) and large (colon) intestine of LTNPs. In LTNPs with chronic infection, the colon had consistently higher viral levels than did the jejunum. The colon also had higher percentages of viral target cells (memory CD4(+) CCR5(+) T cells) and proliferating memory CD4(+) T cells than did the jejunum, whereas markers of cell activation were comparable in both compartments. These data indicate that the large intestine is a major viral reservoir in LTNPs, which may be the result of persistent, latently infected cells and higher turnover of naive and central memory CD4(+) T cells in this major immunologic compartment.

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    • "Residual virus can be found in a variety of tissues in individuals on cART, including the central nervous system (CNS) [3], [4] and the gut-associated lymphoid tissue (GALT). Viral levels in the GALT are still measurable in HIV-1 patients on long-term successful ART [5] and we have shown that the large intestine (where most GALT resides) can harbor much virus, even in SIV-infected animals with low or undetectable viremia [6]. An advantage of animal models is the ability to sample tissues more extensively than is typically feasible in a clinical setting, allowing assessment of residual virus, and the effects of combination treatment strategies in compartments other than blood. "
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    ABSTRACT: Objectives Viral reservoirs–persistent residual virus despite combination antiretroviral therapy (cART)–remain an obstacle to cure of HIV-1 infection. Difficulty studying reservoirs in patients underscores the need for animal models that mimics HIV infected humans on cART. We studied SIV-infected Chinese-origin rhesus macaques (Ch-RM) treated with intensive combination antiretroviral therapy (cART) and 3 weeks of treatment with the histone deacetyalse inhibitor, suberoylanilide hydroxamic acid (SAHA). Methods SIVmac251 infected Ch-RM received reverse transcriptase inhibitors PMPA and FTC and integrase inhibitor L-870812 beginning 7 weeks post infection. Integrase inhibitor L-900564 and boosted protease inhibitor treatment with Darunavir and Ritonavir were added later. cART was continued for 45 weeks, with daily SAHA administered for the last 3 weeks, followed by euthanasia/necropsy. Plasma viral RNA and cell/tissue-associated SIV gag RNA and DNA were quantified by qRT-PCR/qPCR, with flow cytometry monitoring changes in immune cell populations. Results Upon cART initiation, plasma viremia declined, remaining <30 SIV RNA copy Eq/ml during cART, with occasional blips. Decreased viral replication was associated with decreased immune activation and partial restoration of intestinal CD4+ T cells. SAHA was well tolerated but did not result in demonstrable treatment-associated changes in plasma or cell associated viral parameters. Conclusions The ability to achieve and sustain virological suppression makes cART-suppressed, SIV-infected Ch-RM a potentially useful model to evaluate interventions targeting residual virus. However, despite intensive cART over one year, persistent viral DNA and RNA remained in tissues of all three animals. While well tolerated, three weeks of SAHA treatment did not demonstrably impact viral RNA levels in plasma or tissues; perhaps reflecting dosing, sampling and assay limitations.
    PLoS ONE 07/2014; 9(7):e102795. DOI:10.1371/journal.pone.0102795 · 3.23 Impact Factor
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    • "Regardless of the route of transmission, the intestinal tissue, being a major site of viral replication, is rapidly affected by a conspicuous CD4þ T-cell depletion after primary infection (Mattapallil et al, 2005; Schneider et al, 1995; Wang et al, 2007). CD4þ T cells fail to fully repopulate the gastrointestinal tract despite an effective antiretroviral therapy (ART) (Chun et al, 2008), and the virus is detected in the small and large intestines although absent from blood circulation (Ling et al, 2010). Microbial translocation, revealed by circulating LPS during chronic HIV infection, testifies the continuous damage of this tissue (Brenchley et al, 2006; Redd et al, 2009). "
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    ABSTRACT: The gastrointestinal tract is a principal route of entry and site of persistence of human immunodeficiency virus type 1 (HIV-1). The intestinal mucosa, being rich of cells that are the main target of the virus, represents a primary site of viral replication and CD4(+) T-cell depletion. Here, we show both in vitro and ex vivo that HIV-1 of R5 but not X4 phenotype is capable of selectively triggering dendritic cells (DCs) to migrate within 30 min between intestinal epithelial cells to sample virions and transfer infection to target cells. The engagement of the chemokine receptor 5 on DCs and the viral envelope, regardless of the genetic subtype, drive DC migration. Viruses penetrating through transient opening of the tight junctions likely create a paracellular gradient to attract DCs. The formation of junctions with epithelial cells may initiate a haptotactic process of DCs and at the same time favour cell-to-cell viral transmission. Our findings indicate that HIV-1 translocation across the intestinal mucosa occurs through the selective engagement of DCs by R5 viruses, and may guide the design of new prevention strategies. →See accompanying article
    EMBO Molecular Medicine 05/2013; 5(5). DOI:10.1002/emmm.201202232 · 8.67 Impact Factor
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    • "The anatomical reservoir in GALT has been examined in a small study revealing lower levels of HIV DNA in rectal tissue in LTNP compared to progressors [158]. However, an SIV macaque model demonstrated that colon mucosa and associated lymph nodes are a major SIV reservoir even in controllers [159]. "
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    ABSTRACT: In the early days of the HIV epidemic, it was observed that a minority of the infected patients did not progress to AIDS or death and maintained stable CD4+ cell counts. As the technique for measuring viral load became available it was evident that some of these nonprogressors in addition to preserved CD4+ cell counts had very low or even undetectable viral replication. They were therefore termed controllers, while those with viral replication were termed long-term nonprogressors (LTNPs). Genetics and virology play a role in nonprogression, but does not provide a full explanation. Therefore, host differences in the immunological response have been proposed. Moreover, the immunological response can be divided into an immune homeostasis resistant to HIV and an immune response leading to viral control. Thus, non-progression in LTNP and controllers may be due to different immunological mechanisms. Understanding the lack of disease progression and the different interactions between HIV and the immune system could ideally teach us how to develop a functional cure for HIV infection. Here we review immunological features of controllers and LTNP, highlighting differences and clinical implications.
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