Viral Sanctuaries during Highly Active Antiretroviral Therapy in a Nonhuman Primate Model for AIDS

North, Thomas W.; Higgins, Joanne; Deere, Jesse D.; Hayes, Timothy L.; Villalobos, Andradi; Adamson, Lourdes; Shacklett, Barbara L.; Schinazi, Raymond F.; Luciw, Paul A.

doi:10.1128/jvi.02356-09

Cited by 155 publications

(184 citation statements)

References 66 publications

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“…This hypothesis builds first on the link between the size of the reservoir and the degree of inflammation, arguing that persistent virus production during ART could sustain immune activation (IA) and downstream pathological consequences (23, 24), and second on drug distribution studies in animal models of AIDS in which drug concentrations in tissues have been shown to differ from PB levels (25,26). Supporting this argument is the observation that some (but not all) intensification schemes with the integrase inhibitor raltegravir demonstrated a transient increase in 2LTR circles and decreases in IA, suggesting ongoing replication in a tissue site that is not reflected by measures in PB (27,28).…”

mentioning

confidence: 99%

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Fletcher

Staskus²,

Wietgrefe³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

587

608

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Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution.drug levels | pharmacokinetics | FDC network C ombination antiviral therapy (ART) to suppress HIV-1 replication and reduce plasma viremia to below the limits of detection in peripheral blood (PB) has reduced mortality and dramatically improved quality of life for patients. However, immune reconstitution, measured by changes in the size of populations of CD4 T cells, is often incomplete, even after years of therapy (1-3). During apparently effective therapy, CD4 T-cell populations in PB mononuclear cells (PBMCs), lymph node (LN), and gut-associated lymphoid tissue (GALT) remain abnormally low and innate and adaptive immunity is not fully restored (4). Levels of T-cell activation and innate system activation are often higher than that observed in well-matched uninfected adults (5, 6). These persistent abnormalities may contribute to abnormal vaccine responses (7, 8), a higher than normal incidence of non-AIDS-related cancers (9, 10) and increased risk for clinical conditions associated with chronic inflammation (e.g., cardiac disease, clotting disorders, pulmonary hypertension, emphysema, and stroke) (11-18). Thus, improvements over current approaches to treatment of HIV infection that more fully restore normal immune function might significantly improve health and life expectancy.To that end, we explore here the hypothesis that antiretroviral drug (ARV) concentrations might be insufficient to fully suppress replication in the lymphoid tissue compartments, which are the principal sites where virus is produced, stored as complexes on the follicular dendritic cell network (FDCn) (19-21), and persists in latently infected cells during ART (19,20,22). This hypothesis builds first on the link between the size of the reservoir and the degree of inflammation, arguing that persistent virus production during ART could sustain immune activation (IA) and downstream pathological consequences (23, 24), and second on drug distribution studies in animal models of AIDS in which ...

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mentioning

confidence: 99%

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Fletcher

Staskus²,

Wietgrefe³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

587

608

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“…Plasma viremia decreased to < 30 copies/ml within 7-14 days of cART, even when pre-cART pVL was 10 and pigtailed macaques it can take months to reduce viremia to < 100 copies/ml and low level spikes of measurable viremia ''blips'' may persist in some animals. 4,11,12,27 Generally, Ch-RM have lower pVL than other NHPs after SIV infection, which is closer to those of HIV-1 patients. 13,14,18 Accumulating data indicate that the levels of viral replication, reflected by pVL prior to initiation of antiretroviral therapy, influence the facility of viral suppression with cART.…”

Section: Discussionmentioning

confidence: 58%

“…However, even with prolonged administration of cART regimens that suppress viral replication to below the quantitation limits of clinical assays (< 50 vRNA copies/ml plasma), the virus persists. [1][2][3][4] Understanding HIV-1 persistence in patients on cART is essential for developing strategies to permanently suppress viral replication to achieve a functional cure (no viral rebound upon discontinuation of cART) or complete viral eradication. However, examining residual virus in HIV patients is challenging due to ethical and practical difficulties in obtaining the necessary specimens, particularly tissue samples.…”

Section: Introductionmentioning

confidence: 99%

“…Nonhuman primate (NHP) models, which allow for longitudinal tissue sampling, provide advantages for such tissue-based studies examining viral persistence. NHP such as cynomolgus macaques (Macaca fascicularis), [5][6][7] Indian rhesus macaques (Macaca mulatta), 4,[8][9][10] and pigtailed macaques (Macaca nemestrina) 11,12 have been widely used for pathogenesis, vaccine, and reservoir studies. However, using available cART regimens for prolonged periods of time, it has proven difficult to consistently and durably suppress viral replication to < 50 vRNA copies/ ml in treated animals, a level of suppression that mimics clinical HIV-1 patients on cART (< 50 copies/ml), making improved NHP models a priority.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of Combination Antiretroviral Therapy on Chinese Rhesus Macaques of Simian Immunodeficiency Virus Infection

Ling

Rogers²,

Johnson³

et al. 2013

AIDS Research and Human Retroviruses

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Definitive treatment of HIV infection remains a critical but elusive goal, with persistence of residual virus even in the face of prolonged administration of suppressive combination antiretroviral treatment (cART) providing a source for recrudescent infection if treatment is stopped. Characterization of the residual virus and devising strategies to target it for eradication are key goals in HIV treatment research. Indian rhesus macaques (In-RM) infected with SIVmac have been widely used in such research. However, it has proven challenging to achieve and sustain clinically relevant levels of suppression (< 30 vRNA copies/ml plasma) with cART in such models. As ease of viral suppression by cART is related to pretreatment levels of viral replication, and levels of replication of SIVmac239/251 are lower in Chinese rhesus macaques (Ch-RM) than in In-RM, we evaluated cART administration to SIVmac-infected Ch-RM as a potential model for studies of residual virus and eradication strategies. Four SIVmac239-infected Ch-RM received cART including reverse transcriptase inhibitors PMPA/FTC and integrase inhibitor L-870812 daily for 8 weeks. Plasma viral loads were promptly reduced to < 30 copies/ml upon initiation of cART. Cell-associated SIV DNA levels in lymphocytes from the gut were also significantly reduced. Jejunal and colonic CCR5 + CD4 + mucosal memory T cells increased significantly; restoration of these cells was associated with reductions in immune activation. In conclusion, cART effectively suppressed viral replication to < 30 vRNA copies/ml in SIVmac239-infected Ch-RM, reducing immune activation and restoring mucosal immune cell populations. SIVmac239-infected Ch-RM may be a useful model for studying responses to cART and persistent tissue reservoirs and evaluating candidate eradication strategies to cure HIV infection.

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“…In an SIV model with FTC and tenofovir therapy, it was shown that resting CD4+ T lymphocytes from lymph nodes but not thymocytes contribute to the reservoir (Shen et al, 2003). While viral DNA was detected in multiple tissues of RT-SHIV-infected animals with and without triple therapy, very little or no viral RNA was detected in these tissues during complete suppression (North et al, 2010;Ambrose et al, unpublished results). Lymphoid and gastrointestinal tissues showed the highest level of viral DNA in virally suppressed animals, suggesting that they consist of the majority of the viral reservoir.…”

Section: Evaluating Viral Reservoirs During Antiretroviral Therapymentioning

confidence: 99%

Use of Animal Models for Anti-HIV Drug Development

Ambrose¹

2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

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Viral Sanctuaries during Highly Active Antiretroviral Therapy in a Nonhuman Primate Model for AIDS

Cited by 155 publications

References 66 publications

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues

Effect of Combination Antiretroviral Therapy on Chinese Rhesus Macaques of Simian Immunodeficiency Virus Infection

Use of Animal Models for Anti-HIV Drug Development

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