A T and B Cell Therapeutic Countermeasure to Functionally Cure Lentiviral Infection

About This Grant

PROJECT SUMMARY HIV-1 establishes life-long infection that requires continual antiretroviral therapy (ART) to suppress virus replication. Although long-acting ART promises to improve treatment adherence, a therapeutic countermeasure for suppressing HIV-1 infection without lifelong treatment is needed. This type of HIV cure strategy is called a functional cure. In preliminary studies, we designed a series of immunogens that elicit serum nAbs against heterologous viruses in macaques. The nAbs target the second variable region (V2) Apex on HIV-1 envelope, with binding orientations similar to known human V2 Apex broadly nAbs (bnAbs). This B cell targeting countermeasure is the main innovation of our study. Furthermore, we developed an integrase-deficient lentiviral vector (IDLV) that delivers the viral gag gene to elicit specific CD8 T cells. Induction of these CD8 T cells suppressed viremia to undetectable levels in macaques. Our conceptual innovation is to combine both successful countermeasures together to potently and durably control viremia. The objective of this study is to sustainably suppress HIV viremia by combining a CD8 T cell countermeasure that controls viremia with a B cell countermeasure that elicits neutralizing antibodies (nAb) that are active against many heterologous viruses. The proposal has three specific aims. First, to determine the immunogenicity of the combination T cell and V2 Apex nAb-inducing countermeasure in ART-suppressed, SHIV-infected macaques by comparing the neutralization breadth of serum and monoclonal Abs, as well as CD8 T cell cytokine production and inhibition of virus-infected cells among a mock-treated group, the countermeasure treated group, and previous groups of uninfected macaques. Second, to demonstrate sustained viral suppression without ART by the administration of the therapeutic countermeasure in chronically SHIV-infected macaques by assessing changes in CD4 T cells and virus nucleic acid over time following ART cessation. Mechanistic studies will be done in macaques to show CD8 T cell and V2 apex nAb contributions to viral suppression. Third, to determine the impact of ART on the frequency of V2 Apex-specific B cells in people living with HIV-1 (PLWH) using a 10X Genomics BEAM-seq sequencing and AI/ML approach to identify V2 Apex B cells in PLWH before and during ART. The impact of this study is that it will define a therapeutic countermeasure that can permanently suppress viremia, taking the first steps toward a functional cure for the nearly 40 million people currently living with HIV-1.