Recent successes in achieving a functional cure for HIV infection are redirecting the field to examine therapeutic regimens to eliminate latent virus reservoirs. Cocktails of antiretroviral (ART) drugs have been successful in reducing viremia to undetectable levels in HIV+ adult subjects that have access to the therapy. Yet, the drugs are unable to eliminate latent virus in certain cellular and tissue compartments. While ART is the standard of care for HIV+ mothers and their infants who are exposed to infection risk before, during, and after birth, the field has not addressed an extension of ART therapy that could abate virus expansion and eliminate established latent viral reservoirs. A proven nonhuman primate model for perinatal infection that examines new therapeutic regimens that can be instituted at or immediately following infection is needed to address whether it is possible to eradicate HIV. The objective of the proposed project is to adapt an established model of persistent pathogenic SHIV infection in newborn rhesus macaques to study the effects of very early therapies with or without ART. Understanding the full contribution of antibodies, including neutralizing antibodies (NAbs), in HIV-1 infection remains one of the highest research priorities. Passively transferred NAbs can provide sterilizing immunity in nonhuman primate models and when present early in infection can change the course of SIV or SHIV infection stabilizing the adaptive immune response to prevent viral divergence. Studies designed to define how well antibodies can affect the viral reservoir are the next steps in the field. The central hypothesis of this research proposal is that therapeutic treatment with potent neutralizing human monoclonal antibodies (NmAbs) will result in highly controlled or undetectable viral reservoirs in babies born to HIV-infected mothers. Newborn rhesus macaques when infected orally with SHIV-SF162P3 develop widely dispersed and rapidly diverging viral quasispecies in blood and tissues within the first few days to weeks of infection resulting in high and persistent viremia. However, in newborn macaques that receive passive treatment with neutralizing IgG, disease and death is prevented demonstrating that NAbs present during acute infection can alter the dynamics of infection and reduce viral spread and establishment of the reservoir. Once the timing and characterization of latent viral pools are characterized, the project will define the roles that NmAbs play in (i) controlling virus load, (ii) affecting the size of the integrated viral reservoir, and (iii) influecing the development of effective adaptive immune responses. The project will also examine whether NmAb cocktails that are effective when used alone can further augment the ability of ART resulting in more potent and durable reduction in latency. The contribution of the proposed research is expected to define the advantage of passively transferred neutralizing antibodies as therapeutics in a perinatal setting either alone or in concert with ART.
The global HIV pandemic demands immediate and continuous efforts to address those living with viral infections or under imminent risk of infectio. The proposed work promises hope for identifying new approaches to achieving a functional cure for HIV-1 infection by adapting a proven animal model of perinatal HIV infection to eliminate latent viral reservoirs. If the objectives of this project are realized and new therapeutic regimen are defined, it will be a major advance for the field.
|Hessell, Ann J; Jaworski, J Pablo; Epson, Erin et al. (2016) Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques. Nat Med 22:362-8|