Elite controllers as a model for a cure of HIV-1 infection

About This Grant

Abstract: A cure for HIV-1 infection, previously considered elusive, has now been documented in several individuals who underwent a hematopoietic stem cell transplant from donors with the CCR532 gene defect, providing proof-of-principle evidence that curative interventions for HIV-1 infection can be successful. However, curative approaches based on toxic allogeneic stem cell transplantation can only be used in highly selected individuals who suffer from malignant comorbidities. An alternative form of a “functional cure” for HIV-1 infection is exemplified by elite controllers, individuals who maintain undetectable levels of HIV-1 replication in the absence of antiretroviral therapy for extended periods of time. Through detailed molecular assessments of the viral reservoir profile in our previous work, we have demonstrated that HIV-1 reservoir cells in elite controllers display marked footprints of immune selection, most clearly evidenced by the selective presence of intact proviruses in heterochromatin regions. These observations strongly suggest that in elite controllers, the human immune system can recognize, target and eliminate HIV-1 reservoir cells. However, the mechanisms underlying immune targeting of the HIV-1 reservoir cell pool remain undefined. Here, we propose to address this central question in detail using a combination of advanced, high-resolution, analytic techniques in a large cohort of elite controllers that have previously been studied in our laboratory and for which a detailed characterization including the frequencies of intact proviruses annotated with corresponding proviral integration sites, is already available. In Specific Aim 1, we will deeply interrogate HIV-1 reservoir cells from elite controllers through a novel single-cell microfluidics technology designed to capture the surface phenotype and the transcriptional signature of participant-derived cells that harbor intact or defective proviruses directly ex vivo; these assays will be highly informative for unraveling specific immunological vulnerabilities of the viral reservoir cell pool, and may reveal imprints of antiviral immune activity operational in elite controllers. Specific Aim 2 will focus on using single-cell next-generation sequencing technologies to evaluate genomic, epigenetic, and epi-transcriptomic characteristics of individual HIV-1-infected cells from elite controllers to evaluate correlates of immune adaptation, and possibly, of immune evasion, in reservoir cells from elite controllers. In Specific Aim 3, we will focus on how NK cells can contribute to immune selection pressure against HIV-1 reservoir cells in elite controllers, using a pipeline of assays designed to evaluate transcriptional signatures, genomic variations, immunogenetic properties and functional characteristics of NK cells in participant-derived samples; these studies will test the hypothesis that HIV-specific T cells and NK cells represent complementary arms of antiviral immune activity that, through collaborative efforts, are inducing the remarkable clinical outcome of natural immune-mediated HIV control.