Primate Model Of HIV Infection Research Articles

Coreceptor use in nonhuman primate models of HIV infection

SIV or SHIV infection of nonhuman primates (NHP) has been used to investigate the impact of coreceptor usage on the composition and dynamics of the CD4+ T cell compartment, mechanisms of disease induction and development of clinical syndrome. As the entire course of infection can be followed, with frequent access to tissue compartments, infection of rhesus macaques with CCR5-tropic SHIVs further allows for study of HIV-1 coreceptor switch after intravenous and mucosal inoculation, with longitudinal and systemic analysis to determine the timing, anatomical sites and cause for the change in envelope glycoprotein and coreceptor preference. Here, we review our current understanding of coreceptor use in NHPs and their impact on the pathobiological characteristics of the infection, and discuss recent advances in NHP studies to uncover the underlying selective pressures for the change in coreceptor preference in vivo.

Relationship of Pneumocystis jiroveci Humoral Immunity to Prevention of Colonization and Chronic Obstructive Pulmonary Disease in a Primate Model of HIV Infection

Pulmonary colonization by the opportunistic pathogen Pneumocystis jiroveci is common in HIV(+) subjects and has been associated with development of chronic obstructive pulmonary disease (COPD). Host and environmental factors associated with colonization susceptibility are undefined. Using a simian-human immunodeficiency virus (SHIV) model of HIV infection, the immunologic parameters associated with natural Pneumocystis jiroveci transmission were evaluated. SHIV-infected macaques were exposed to P. jiroveci by cohousing with immunosuppressed, P. jiroveci-colonized macaques in two independent experiments. Serial plasma and bronchoalveolar lavage (BAL) fluid samples were examined for changes in antibody titers to recombinant Pneumocystis-kexin protein (KEX1) and evidence of Pneumocystis colonization by nested PCR of BAL fluid. In experiment 1, 10 of 14 monkeys became Pneumocystis colonized (Pc(+)) by 8 weeks post-SHIV infection, while 4 animals remained Pneumocystis colonization negative (Pc(-)) throughout the study. In experiment 2, 11 of 17 animals became Pneumocystis colonized by 16 weeks post-SHIV infection, while 6 monkeys remained Pc(-). Baseline plasma KEX1-IgG titers were significantly higher in monkeys that remained Pc(-), compared to Pc(+) monkeys, in experiments 1 (P = 0.013) and 2 (P = 0.022). Pc(-) monkeys had greater percentages of Pneumocystis-specific memory B cells after SHIV infection compared to Pc(+) monkeys (P = 0.037). After SHIV infection, Pc(+) monkeys developed progressive obstructive pulmonary disease, whereas Pc(-) monkeys maintained normal lung function throughout the study. These results demonstrate a correlation between the KEX1 humoral response and the prevention of Pneumocystis colonization and obstructive lung disease in the SHIV model. In addition, these results indicate that an effective Pneumocystis-specific memory B-cell response is maintained despite progressive loss of CD4(+) T cells during SHIV infection.

HIV-1/AIDS vaccine development: are we in the darkness before the dawn?

HIV-1/AIDS vaccine development: are we in the darkness before the dawn?

Role of immune activation in HIV pathogenesis

T-cell activation has long been considered a central mediator of HIV pathogenesis. High T-cell activation levels predict more rapid disease progression in untreated patients and decreased treatment-mediated CD4+ T-cell gains during antiretroviral therapy, independent of plasma HIV RNA levels, and may be the primary feature distinguishing pathogenic from nonpathogenic primate models of HIV infection. Studies in animal models and individuals with HIV infection continue to enhance our understanding of how T-cell activation causes immunodeficiency during HIV infection. The goal of these studies is to identify specific mechanisms that can be targeted by novel immune-based therapies for patients who have thus far been unable to recover normal immune function despite years of antiretroviral therapy. Although most immune-based therapies targeting T-cell activation have been unsuccessful to date, recent scientific developments have focused attention on specific pathways that may be exploited by future generations of immune-based therapies.

Rational Design of AIDS Vaccines

Development of an effective vaccine against HIV has posed significant challenges to the scientific community. Lack of knowledge about the molecular pathogenesis of this disease, and the absence of naturally occurring, protective immune responses, which is attributed in large part to the diversity of the viral envelope and multiple escape mechanisms, have made it difficult to design successful candidates. Recent studies of the envelope have suggested that it is possible to enhance immunogenicity of the envelope by improving the breadth of the neutralizing antibody response and by stimulating cell-mediated immunity. This relies on an understanding of the structure of HIV Env and the use of site-specific mutation to create novel immunogens. Based on structural and functional data, our lab has developed DNA and adenoviral vectors which express envelope proteins containing alterations to regions in the variable loop to better control tropism and improve immunogenicity. These modified HIV genetic vaccine candidates have been tested in combination with Gag, Pol, and Nef immunogens, and shown to improve the potency of cellular and humoral immune responses in primates. An initial Phase I trial (VRC 004) dose escalation study to test a DNA vaccine composed of a 4-plasmid combination of clade B gag/pol/nef with clades A, B, and C envelope was recently completed in 50 healthy adults in the U.S. CD4+ and CD8+ T cell responses were detected in the majority of vaccinees using IFN-(ELISpot) and flow cytometric detection of intracellular IL-2 or IFN-γ. HIV-specific antibody response was detected in about one third of vaccinees. Combination modality regimens using a DNA vaccine prime followed by a viral vector boost have shown promise in nonhuman primate models of HIV infection. Phase I clinical trials to test the safety and immunogenicity of an adenoviral vaccine expressing proteins similar to the DNA, and a DNA prime, adenoviral boost regimen are in progress. The initial adenoviral vector vaccine uses an Ad5 serotype vector. However, pre-existing immunity can mitigate the efficacy, so alternate serotypes and modifications to the adenoviral fiber regions are being explored. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005