Animal Models of HIV Reservoirs
Simian models of HIV infection have been developed that have the potential to address aspects of viral persistence, residual replication, latency and anatomic reservoirs. These models can be used to perform controlled studies that are not feasible in humans and test new strategies aimed at reducing viral reservoirs or inducing a functional cure.
T o study the potential eradication of HIV, well characterized and rigorous animal models are necessary to first exhaustively identify reservoirs of latent virus, then ensure that these reservoirs can be either purged or reduced by new strategies. At a time when antiretroviral therapy (ART) allows patients to live better and longer lives, potentially harmful investigations or treatments must first be tested in animals.
Future of Humans is in Apes
The two primary species of macaques being used in the antiretroviral studies are rhesus (Macaca mulatta) and pig-tailed (Macaca nemestrina). Pathogenic strains of SIV, such as SIVmac239, are used in several models because the high level of viral replication and rapid disease progression lead to a reproducible, robust model and a shorter evaluation time.
SIV is susceptible to NRTIs, some Protease Inhibitors, and Raltegravir.
The Baltimore group of Janice Clements (1) has developped an accelerated SIV macaque ART model based on a consistent, accelerated SIV macaque model characterized by high viral load in the plasma and CSF and the development of AIDS and CNS disease in 3 months.
Beginning at 12 days postinoculation, ART allows a 5 log10 drop in viremia levels for treated versus not treated animals. As in humans, this decline is biphasic. The frequency of resting CD4+ T cells in peripheral blood harboring replication-competent virus shows an initial decay similar to that observed in HIV-1-infecetd humans on ART.
At 80 days post inoculation., there are 8–10 latently infected resting CD4+ T cells per million resting CD4+ T cells in the blood. These numbers decline gradually to approximately one latently infected resting CD4+ T cells per million by 175 days post inoculation.
When resting CD4+ T cells from pooled lymphoid tissue (cervical lymph nodes, gut lymph nodes, spleen...) were analysed, the frequencies of latently resting CD4+ T cells were not significantly different between tissues in ART treated macaques.
Viral RNA in brain measured by quantitative RT PCR is undetectable in treated animals, but viral DNA levels are not different from those seen in untreated SIV-infecetd macaques. Furthermore, continued CNS inflammation was evidenced by measuring levels of several biological markers.
This model, thus demonstartes that the CNS contains a stable SIV DNA reservoir in ART treated macaques and suggests that adjunctive therapies to prevent ongoing CNS inflammation will have to be developed.
A Model for NNRTIS
Because the NNRTIs are specific for HIV-1, SIV is not susceptible to this class of antiretrovirals (2). As a result, the SIV macaque model is limited by the inability to analyze viral persistence during treatment with this clinically important ART regimen. In an attempt to generate a nonhuman primate animal model of HIV-1 that is susceptible to the NNRTIs, a chimeric virus was generated consisting of the SIVmac239 backbone containing the HIV-1 reverse transcriptase (RT-SHIV).
Infection of rhesus macaques with RT-SHIV results in the AIDSlike symptoms and pathology that is observed in SIV infection. Unlike SIV, RT-SHIV is susceptible to nevirapine and efavirenz. This model was used to measure the distribution of vRNA and vDNA in tissues from treated macaques. The results demonstrated widespread distribution of both vRNA and vDNA in many tissue compartments, especially in the gastrointestinal tract and several other lymphoid tissues, despite plasma virus levels below 50 copies per ml.
Another strain of RT-SHIV has also been used to study NNRTI-based HAART regimens in pig-tailed macaques. This virus, designated RT-SHIVmne, is sensitive in vitro to several NRTIs as well as the NNRTIs efavirenz and nevirapine. A genotypically well characterized stock of RT-SHIVmne was used to study population dynamics in macaques. This study analyzed viral evolution, including resistance to antiretrovirals, by tracking viral genomes during efavirenz monotherapy followed by the addition of PMPA and FTC . Genotypic tracking of virus in this model might determine tissue sites of persistent virus, providing
details of residual replication and viral latency that will be critical for HIV-1 eradication.
An appropriate model of HIV-1 should be susceptible to current ART regimens, share cellular tropism, and have similar disease manifestations as HIV-1 in humans. Several models have been developed and each has particular strengths. These models have the advantage of allowing studies that are not feasible in humans, as the study of high-risk regimens aimed at eliminating the latent reservoir and preventing any residual replication.
1- Clements JE, Gama L, Graham DR et al. A simian immunodeficiency virus macaque model of highly active antiretroviral treatment: viral latency in the periphery and the central nervous system. Current Opinion in HIV and AIDS 2011, 6:37–42
2- Deere JD, Schinazi RF, North TW. Simian immunodeficiency virus macaque models of HIV latency. Current Opinion in HIV and AIDS 2011, 6:57–61
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Key words: HIV Elite Controllers, HIV animal models, HIV functional cure, humanized mouse