Life-long treatment is needed to maintain control of HIV infection, and the global sustainability of providing anti-retroviral therapy (ART) to the tens of millions of people in need of treatment is a major concern. The only alternative to this scenario is to develop a strategy that can eradicate HIV from the body. In recent case studies, some individuals either effectively controlled HIV replication following withdrawal of treatment, o completely eliminated the virus. These findings have highlighted the potential for achieving a lasting HIV cure and have generated substantial interest within the field. The hurdle to an HIV cure is the elimination of the latent reservoir of virus. A complete understanding of when the reservoir is established, and the factors affecting its size and stability, is still required, espeially in Sub- Saharan African populations where the disease burden is greatest. In this application we propose that analyzing the composition of the latent reservoir, as a function of time, will inform us as to when the virus was deposited in the reservoir, and possibly its rate of decay. This project will investigate 20 subtype C-infected South African women who were recruited in acute infection, initiated on ART after three years of infection, and who thereafter successfully suppressed HIV replication for at least four years. We will compare the number of intact full-length proviral genomes, as a measure of the total potential reservoir, at two and four years post treatment-initiation, and how it changes over time. Given that many of these integrated viruses may remain latent, we will compare the intact proviral reservoir to the number of replication competent viruses, as measured by using the viral outgrowth assay. We will use deep sequencing approaches to define the evolving viral swarm, from acute infection to the initiation of treatment. We propose that the genetic evolution during three years of infection is sufficient t allow us to map the relative contribution to the latent proviral reservoir over time as well as the time at which the reservoir was established. Lastly, we will look at how immune activation in acute infection, and during treatment, affects the viral composition of the reservoir. This study will estimate the timing of the establishment, size and stability of the latent reservoir in Africa women. We are uniquely placed to carry out this study through access to a cohort of young women monitored from acute infection, and up to five years on ART. Extending latent reservoir observations to cohorts in less-developed countries where host factors, subtype and gender may differ compared to those in developed countries, will inform the development of a more generalizable approach to any potential cure intervention.
The sustainability of the anti-retroviral treatment programs, especially in sub-Saharan Africa, is at serious risk. An HIV cure has recently been shown to be possible, and requires the elimination of the latent reservoir. This project proposes to characterize the latent reservoir in African women on treatment, determine when the latent reservoir is established, and assess host factors that impact the reservoir in this setting.
|Archary, D; Seaton, K E; Passmore, J S et al. (2016) Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel. Mucosal Immunol 9:821-833|
|Garrett, Nigel J; Drain, Paul K; Werner, Lise et al. (2016) Diagnostic Accuracy of the Point-of-Care Xpert HIV-1 Viral Load Assay in a South African HIV Clinic. J Acquir Immune Defic Syndr 72:e45-8|
|Reddy, Kavidha; Ooms, Marcel; Letko, Michael et al. (2016) Functional characterization of Vif proteins from HIV-1 infected patients with different APOBEC3G haplotypes. AIDS 30:1723-9|