Animal Models of HIV Infection

ANIMAL MODELS OF HIV INFECTION

Although many questions concerned with HIV biology were first learned in cultured cell lines infected with HIV or SIV, it became obvious that these cultured lines did not truly mimic the wild-type infections seen in animal models. A number of small rodent models, such as the SCID mouse, were developed and were helpful but somewhat artificial and did not really mimic human disease.

In fact, a significant obstacle in HIV vaccine research has been the difficulty in developing an appropriate animal model with many of the features of human HIV infection. The only animals susceptible to experimental infections with HIV are chimpanzees, Pantroglodytes, and pigtail macaques, Macaca nemestrina. These ani-mals maintain low levels of persistent virus but do not develop clinical manifesta-tions of AIDS. In contrast, Asian monkeys, especially rhesus monkeys from India, are highly susceptible to SIVmac infec-tion and progressively develop an immu-nodeficiency syndrome that is similar to human AIDS. Plasma viral levels during acute and chronic SIVmac251 infection in these animals parallel those observed in humans, with some animals containing virus spontaneously and progressing to disease slowly as in HIV-1 infected human long-term nonprogressors. In con-trast, others maintain high viral loads and behave like human rapid progresses. As in HIV-1 infected humans, the cellular immune response to SIVmac during acute and chronic disease differs significantly, and evidence of immune escape has been well documented. This is particularly true of the mucosal immune system, especially the many CD4⁺ CCR-5+ T cells in the gut-associated lymphoid tissue, the major site of viral replication and of CD4⁺ T-cell depletion in SIV-infected macaques. This also mimics the human disease and thus the SIV macaque model is currently con-sidered the most appropriate animal model for studies on potential protective immune responses against HIV.

A second animal model of HIV vaccine research is based on the use of SIV/HIV hybrid viruses that were engineered to carry the env gene from HIV into the con-tent of the SIV genome. These viruses do replicate in rhesus macaques and after serial macaque passages do lead to the emergence of highly pathogenic SHIV variants that can wipe out circulating CD4⁺ T cells within a few weeks and lead to a lethal immunodeficiency syndrome within a year of infection.

However, the problem has been whether these variants, like SHIV 89.6P, are relevant to HIV infections. For exam-ple, they exhibit an “X4” cellular tropism and are therefore easier to contain by vac-cine-induced immune response than “R5” viruses such as SIV. If we could obtain SHIV strains with R5 tropism, this might be a better model to study.

The real problem with the monkey models is that experiments to evaluate vac-cine efficacy requires challenging the vac-cinated animals with high doses of virus to get 100 percent infection, that is, 10³ – 10⁵ TCID50 equivalent to 5 × 10⁷ SIV RNA cop-ies/ml. This is in marked contrast to natu-ral exposure to HIV in humans wherein the doses of 10³ HIV RNA copies/ml of semi-nal plasma have been reported. However, these results are quite different in mucosal challenge, wherein reported low doses (10–30 TCID50) with SIV results in the same viral and immunological kinetics of infection as high-dose challenges. Thus, this new type of mucosal challenge might change the results of preclinical vaccine efficacy studies in the future.