The recently discovered generation of broadly neutralizing monoclonal antibodies (bNAbs) hold great promise for HIV-1 treatment, prevention and cure. While earlier bNAbs failed to suppress rebound viremia in human trials, recent animal studies have shown that passive infusion of these newer bNAbs can prevent HIV-1 acquisition and potently suppress rebound viremia. Further, a study in SHIV-infected macaques suggested that bNAb administration may enhance HIV-specific T cell responses and reduce proviral DNA levels across tissue compartments. These findings raise enthusiasm for bNAbs' potential role in HIV cure strategies and highlight the need for this exciting data from murine and macaque studies to be validated in humans. The AIDS Clinical Trials Group study A5340 is the first human clinical trial to assess the ability of a bNAb to suppress rebound viremia in the context of an analytical treatment interruption (ATI). A5340 will test the ability of VRC01, a broadly neutralizing antibody to HIV-1 that targets the conserved CD4 binding site to broadly neutralize HIV-1 viruses across clades, to suppress rebound viremia upon interruption of antiretroviral therapy. In this application, we propose to capitalize on this important clinical trial to address complementary questions of how bNAbs modulate host immune responses and alter the viral dynamics of rebound after ATI. In parallel, we will elucidate the currently unclear basic viral and immunological mechanisms of rebound viremia at baseline without bNAb administration, to serve as a comparator. Our overarching hypothesis is that VRC01 administration will enhance the host immune responses and alter the viral dynamics of rebound during treatment interruption. To test this hypothesis, we will perform a series of integrated viral and T cell studes on de-identified clinical samples from A5340 and previously conducted clinical trials of ATI. Specifically, we will test how VRC01 affects (i) the clonality and neutralization sensitivity of rebound viruses and (ii) the timing, functionality and predictive capacity of T cell responses. Together, these studies will characterize the baseline viral dynamics and immune responses of rebound viremia and how immunotherapy with VRC01 alters them. Further, results may identify clinically valuable biomarkers and assays that are predictive of viral rebound. We expect these studies will synergize with the results of A5340 to better characterize the immunomodulatory effects of VRC01 and its potential role in HIV-1 eradication and potentially have broad implications for use of bNAbs across the HIV treatment, prevention and cure agendas.
The immunomodulatory effects of HIV-specific broadly neutralizing antibody (bNAb) therapy in humans are unknown and essential to their use in HIV eradication. Here, we propose to capitalize on the first human trial of the bNAb VRC01 in HIV-infected humans undergoing interruption of their antiretroviral therapy. Determination of the impact of VRC01 on the viral dynamics and immune pressures of viral rebound will have implications for the design and assessment of future immunotherapy trials and the role of bNAbs in HIV cure strategies.
| Salantes, D Brenda; Zheng, Yu; Mampe, Felicity et al. (2018) HIV-1 latent reservoir size and diversity are stable following brief treatment interruption. J Clin Invest 128:3102-3115 |
| Bar, Katharine J; Sneller, Michael C; Harrison, Linda J et al. (2016) Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. N Engl J Med 375:2037-2050 |
