Non Human Primate Models for HIV Cure Research
A recent Viewpoint article published in Retrovirology (1) by the Italian group of researchers lead by Andrea Savarino comments on the recent findings of potential functional cures of AIDS in macaque models (2,3) and on a new simian AIDS model that could be interesting to test strategies aimed at HIV eradication or functional cure. We took this opportunity to ask Doctor Savarino to tell us a little bit more about his research plans.
Alain Lafeuillade: What are currently the main non human primate models of persistent HIV infection and their respective advantages and disadvantages for HIV cure research?
There is a model based on a simian/human immunodeficiency virus chimaera (SHIV) expressing HIV-1 reverse transcriptase. This model has been developed at the University of California at Davis and, apart from using NRTIs to which all simian lentiviruses are susceptible, it may exploit NNRTIs, towards which simian lentiviruses are highly resistant. Another model, developed by researchers at John Hopkin’s University, has an important brain reservoir persisting during therapy, due to the use of a neurotropic virus. However, this model adopted a four-drug combination that is not used in humans. Moreover, both of these models do not allow complete control of ongoing viral replication. In this regard, researchers at the University of Pittsburgh have described an impressive level of spontaneous drug-free control of viral replication in rhesus macaques following inoculation of a virus derived from African green monkeys and different from the sooty mangabay-derived viruses that normally induce AIDS in macaques. These findings may allow opening a window into the future, showing how a “functional cure” may look like. However, this finding is not directly translatable to humans, in that they did not apply any specific therapeutic interventions able to alter the natural course of the disease.
AL: Could you describe your model and its advantages over others?
AS: First, our interventions were done in animals infected with a simian lentivirirus, that is, SIVmac251, which is able to induce a disease closely recapitulating HIV immunopathogenesis in humans. Second, the therapeutic regimen that we adopted (a five-drug regimen dubbed H-iART; i.e. tenofovir/emtricitabine/raltegravir/darunavir/r/maraviroc) has already been used in humans and is thus likely to mimic the conditions observed in HIV-infected individuals under ART. Moreover, our therapy is able to keep the virus under check for prolonged periods both in plasma and in anatomical sanctuaries such as the lymph nodes, rectal tissues and cerebrospinal fluid, thus allowing the isolation of the effects of additional strategies aimed at targeting the viral latent reservoirs. In this regard, we showed that spontaneous control of viral replication is possible in this model, after suspension of a therapy containing antiretroviral and non-antiretroviral molecules aimed at targeting the viral reservoir.
AL: What is the particular contribution of Maraviroc in this model?
AS: Simian lentiviruses have a higher viral burst size (which may be intended as the average number of viral particles produced by an infected cell), thus raising the need to inhibit viral replication at multiple steps since the early stages. As one main co-receptor in vivo for SIVmac251 attachment to target cells is CCR5, we used maraviroc for maintenance of prolonged undetectable viral loads.
AL: How can you explain the dramatic impact of the combination used on tissue viral DNA?
AS: This was one unexpected effect that we detected after addition of maraviroc. This may be interpreted as an effect of maraviroc on ongoing viral replication, lowering the content of non-integrated viral DNA, but also as a specific effect of maraviroc on the viral reservoir. We showed that maraviroc decreases activation-driven proliferation of the central and transitional memory T-cells, encompassing the most important latent viral reservoir in lymphocytes. The mathematical model of Rong and Perelson that we adopted to explain our results suggests that decreased proliferative ratios are per se sufficient to restrict the number of infected cells.
AL: Is there any hope for a functional cure deriving from the macaque AIDS models?
AS: Yes, definitely! We published recently in PLoS Pathogens an impressive level of viral containment following suspension of H-iART plus the “antimemory” drug auranofin, followed by a short H-iART cycle at viral rebound (2). Last year, at the Saint Martin Workshop on HIV Persistence during therapy, we presented preliminary results indicating spontaneous control of viremia following therapy suspension by using another drug in combination with the H-iART/auranofin strategy. This drug is BSO, which is able to kill some of the cells escaping latency and becoming productively infected. On the other hand, an entirely different strategy has been published in Retrovirology, showing that prolonged suboptimal antiretroviral treatment of macaques resulted in three functional cures out of four treatment subjects following therapy suspension.
AL: What are your plans for the future?
AS: We think that we have already played our part in the establishment of animal models and now would like to focus our efforts on research for a functional cure that could theoretically be transferred to humans. First of all, we are currently focussing on treatment protocol optimization, hoping to be able to start a clinical trial in 2013. Moreover, I think that it will be interesting to find out whether there are common mechanisms sparked by the different approaches that have so far been able to result in “functional cures” both in macaques and in humans.
1-Savarino A, Garaci E. Therapeutic imprinting of the immune system:towards a remission of AIDS in primates? Retrovirology 2012; 9:75 doi:10.1186/1742-4690-9-75
2-Shytaj IL, Norelli S, Chirullo B, et al. A Highly Intensified ART Regimen Induces Long-Term Viral Suppression and Restriction of the Viral Reservoir in a Simian AIDS Model. PLoS Pathog 2012; 8(6): e1002774. doi: 10.1371/journal.ppat.1002774.
3- Van Rompay KK, Trott KA, Jayashankar K, Geng Y, Labranche CC, Johnson JA,Landucci G, Lipscomb J, Tarara RP, Canfield DR, Heneine W, Forthal DN, Montefiori D, Abel K. Prolonged tenofovir treatment of macaques infected with K65R reverse transcriptase mutants of SIV results in the development of antiviral immune responses that control virus replication after drug withdrawal. Retrovirology.2012 Jul 17;9:57.
Key words: HIV cure, HIV eradication, HIV reservoirs, SIV macaque model, towards an HIV cure.