Elias (Lou) Halvas, PhD, has been awarded funding of $3,617,103 for a five-year R01 grant by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) entitled “Understanding Immune Evasion by HIV-1 Repliclones”. This proposal was submitted in response to the competitive funding opportunity entitled “NIH Research Project Grant Program (Parent R01)” under funding opportunity number PA-20-185.

Despite the efficacy and clinical benefits of effective antiretroviral therapy (ART), a reservoir of cells harboring replication-competent (intact) proviruses usually leads to viral rebound within weeks of stopping ART. Although this HIV reservoir is generally considered to be latent, sensitive PCR-based single copy HIV RNA assays have revealed low-level viremia in individuals on ART, indicating that latency is not absolute or uniform. HIV persists on ART in clonally expanded CD4 T-cells carrying replication-competent proviruses (termed repliclones), which are capable of producing infectious virus and viremia that is not suppressible with ART. The mechanisms involved in clonal outgrowth, persistence and escape from immune-mediated clearance are not defined.

This study will examine the mechanisms of clonal persistence including latency, viral escape mutations to antibodies and cytotoxic T-lymphocytes, and intrinsic clonal resistance to immune-mediated killing, in an effort to gain insight on designing strategies that eliminate repliclones. The work will be carried out by an ongoing, productive, and complementary collaboration between the Halvas and Mellors virology laboratories and the Jones immunology laboratory at Weill Cornell Medicine. The insights gained from this work will be broadly applicable to the development of therapeutic approaches to target the persistent, clonally expanded HIV reservoir that is the main barrier to curing HIV infection.