A new HIV Model Could Help Shed Light on Mechanisms of Viral Host Tropism

 

By Asu Erden

 

To better understand the epidemiology of human diseases, we must identify the immunological mechanisms that govern their transmission and enable their jumping from one reservoir to the next. In this regard, animal models have proven useful. Yet the pathogenic mechanisms enabling the interspecies transmission of many diseases remain elusive. This is the case for the Human Immunodeficiency Virus (HIV). Primate and humanized mouse models have helped shed light on the viral mechanisms of HIV. As far as primate models go, pigtailed macaques have been particularly useful since they present the advantage of better mimicking the pathogenesis of AIDS as seen in humans. However, these macaques are not susceptible to HIV-1 since the virus does not normally cause AIDS in this host species. But Hatziioannou et al. recently provided a new stepping-stone to the field when they published their findings of an HIV-1 infection leading to AIDS in pigtailed macaques in the journal Science.

The team of researchers used a modified HIV-1 that encodes Simian Immunodeficiency Virus (SIV) Vif. The latter protein prevents the action of host-specific antiviral enzymes. By passaging this virus and taking advantage of the lack of key antiviral proteins (e.g. TRIM5) in pigtailed macaques, Hatziioannou and her colleagues were able to successfully infect these animals. In one of them, the virus replicated to reach stable high titers. The team decided to deplete this animal of circulating CD8+ T cells to alleviate immune pressure and allow for higher viral titers, since these cells are believed to contribute to the initial control of viremia. By the fourth passage (P4) of this virus in CD8-depleted macaques, AIDS-like pathogenesis became apparent (e.g. sustained high viremia, immune activation in the gut) and eventually animals fully developed the disease (stark loss of CD4+ T cells).

Hatziioannou et al. confirmed that they had obtained a virus capable of causing AIDS in pigtailed macaques by isolating it from P4 animals and inoculating new CD8-depleted animals. The infected macaques developed AIDS confirming that the researchers had developed a virus capable of triggering a pathogenesis similar to what is seen in humans. Moreover, the key time period for CD8+ T cell-depletion was identified to be the acute phase of infection since depletion at the chronic stage did not yield AIDS-like symptoms.

Several signature mutations in the passaged virus’ genome also reflected that Hatziioannou et al. had successfully adapted the virus to acquire characteristics seen in human HIV-1 infection. Single viral genome sequencing revealed that envelope mutations were essential for the aforementioned adaptation in pigtailed macaques. Of specific interest was a deletion in one of the loops of the envelope protein, which is typical of human lentiviral infections but much more rarely observed in non-human primates. Additionally, an insertion mutation in the transmembrane domain of the HIV-1 Vpu immune evasion protein enabled it to immunologically outcompete macaque tetherin, which normally prevents virions from budding from the host cells.

HIV-1 causes AIDS in humans and chimpanzees. The fact that Hatziioannou et al. were able to develop a model of HIV-1-induced AIDS in pigtailed macaques promises to shed light on the key immunological factors at play in the epidemiology of HIV. Their protocol also reinforces the idea that CD8+ T cells play an essential role in the early stages of the pathogenesis, since macaques had to be depleted of this cell subtype during the acute phase of infection to progress to AIDS. Overall, these results highlight the importance of the arms race between the virus and the host. In four passages, Hatziioannou et al.’s modified HIV-1 virus developed the ability to counteract macaque tetherin. Such evolution is required for the virus to spread to new hosts. In the future, studies of HIV-1 in this pigtail macaque model have the potential to provide insight about new prophylactic vaccines and therapeutic drugs against the virus.