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A small animal model that reproduces human immunodeficiency virus type 1 (HIV-1) pathogenesis may allow modeling of new therapeutic strategies in ways not approachable in mononuclear cell culture. We find that, as in humans, combination antiretroviral therapy (ART) in humanized (hu-) Rag2 −/− γ c −/− mice allows suppression of viremia below the limits of detection and recovery of CD4 + cells, while interruption of ART results in viral rebound and renewed loss of CD4 + T cells. Failure of ART in infected mice is associated with the appearance of drug resistance mutations. The hu-Rag2 −/− γ c −/− mouse may therefore facilitate testing of novel approaches to HIV replication and persistence.

Histone deacetylases (HDACs) act on histones within the nucleosome-bound promoter of human immunodeficiency virus type 1 (HIV-1) to maintain proviral latency. HDAC inhibition leads to promoter expression and the escape of HIV from latency. We evaluated the ability of the potent inhibitor recently licensed for use in oncology, suberoylanilide hydroxamic acid (SAHA; Vorinostat), selective for Class I HDACs, to induce HIV promoter expression in cell lines and virus production from the resting CD4(+) T cells of antiretroviral-treated, aviremic HIV-infected patients. In J89, a Jurkat T cell line infected with a single HIV genome encoding the enhanced green fluorescence protein (EGFP) within the HIV genome, SAHA induced changes at nucleosome 1 of the HIV promoter in chromatin immunoprecipitation (ChIP) assays in concert with EGFP expression. In the resting CD4(+) T cells of antiretroviral-treated, aviremic HIV-infected patients clinically achievable exposures to SAHA induced virus outgrowth ex vivo. These results suggest that potent, selective HDAC inhibitors may allow improved targeting of persistent proviral HIV infection, and define parameters for in vivo studies using SAHA.

A study was conducted to compare the immunocompetence of four commercial broiler strains (Ross 3F8, Ross x Cobb, Ross 308 and Cobb x Cobb (CC)) that were fed either a marginal protein diet (D1) or a high protein diet (D2) for the starter and finisher diets, respectively. Strain CC showed comparatively higher and more persistent antibody titers against sheep red blood cells (SRBC) (P < 0.0182) as well as higher macrophage phagocytic function for SRBC uptake (P = 0.0118) than the other strains. The Ross 308 strain had significantly greater cell mediated immune response, as measured by T-lymphocyte proliferation response to phytohemagglutinin-P (PHA-P), P < 0.04) and Concanavalin-A (Con-A) (P < 0.0281), as well as for the chemotaxis response to formyl-met-leu-phe (P < 0.0019) than the other strains. The diet effect was variable for monocyte-macrophage functions, but birds on the high protein diets showed higher cell- mediated response than the birds on the low protein diets when measured by Con-A and PHA-P responses. An interaction between strains and diets was seen for antibody response with the Ross 308 showing higher titers on D1 while the CC had greater antibody response when raised on D2. These results suggest that genetic differences exist between various commercial broiler chicken lines for cell mediated, humoral and innate immune responses. Furthermore, dietary protein levels appear to influence the immune response levels of broiler chickens but the response obtained varies by strain. The results of these studies imply that immunocompetence is genetically controlled, and, therefore some measures of immunocompetence could be considered as a selection criterion while selecting for performance traits.

Persistent human immunodeficiency virus type 1 (HIV-1) infection of resting CD4 + T cells, unaffected by antiretroviral therapy (ART), provides a long-lived reservoir of HIV infection. Therapies that target this viral reservoir are needed to eradicate HIV-1 infection. A small-animal model that recapitulates HIV-1 latency in resting CD4 + T cells may accelerate drug discovery and allow the rational design of nonhuman primate (NHP) or human studies. We report that in humanized Rag2 −/− γ c −/− (hu-Rag2 −/− γ c −/− ) mice, as in humans, resting CD4 + T cell infection (RCI) can be quantitated in pooled samples of circulating cells and tissue reservoirs (e.g., lymph node, spleen, bone marrow) following HIV-1 infection with the CCR5-tropic JR-CSF strain and suppression of viremia by ART. Replication-competent virus was recovered from pooled resting CD4 + T cells in 7 of 16 mice, with a median frequency of 8 (range, 2 to 12) infected cells per million T cells, demonstrating that HIV-1 infection can persist despite ART in the resting CD4 + T cell reservoir of hu-Rag2 −/− γ c −/− mice. This model will allow rapid preliminary assessments of novel eradication approaches and combinatorial strategies that may be challenging to perform in the NHP model or in humans, as well as a rigorous analysis of the effect of these interventions in specific anatomical compartments.

A small animal model that reproduces human immunodeficiency virus type 1 (HIV-1) pathogenesis may allow modeling of new therapeutic strategies in ways not approachable in mononuclear cell culture. We find that, as in humans, combination antiretroviral therapy (ART) in humanized (hu-) Rag2(-/-)gamma(c)(-/-) mice allows suppression of viremia below the limits of detection and recovery of CD4(+) cells, while interruption of ART results in viral rebound and renewed loss of CD4(+) T cells. Failure of ART in infected mice is associated with the appearance of drug resistance mutations. The hu-Rag2(-/-)gamma(c)(-/-) mouse may therefore facilitate testing of novel approaches to HIV replication and persistence.

Background Human immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART. Methods Patients with plasma HIV RNA50%) was seen in six volunteers after the addition of RAL and VPA. In 4 of the 6 patients this lack of effect might be attributed to intermittent viremia, low VPA levels, or intermittent study therapy adherence. Overall, there was no effect of the addition of RAL or ENF on low-level viremia measured by SCA. Conclusions The prospective addition of VPA and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia. New approaches such as more potent HDAC inhibition, alone or in combination with intensified ART or other agents that may disrupt proviral latency must be pursued.