R01AI162223

Single Cell Transcriptomics of HIV Persistence and Latency - Summary

Antiretroviral therapy (ART) in HIV-1 infection suppresses viral replication, preserves and improves the CD4+ T cell count, and prevents disease progression. However, treatment with ART is not curative, and interruption of therapy consistently unleashes viral relapse. The persistence of a viral reservoir following ART is the major obstacle to an HIV cure. Proposed "shock and kill" strategies to activate and eliminate the HIV reservoir are currently not informed by a knowledge of the T cell states or lineages that support latency.

One of the greatest challenges in latency research is to distinguish latent cells from non-latent cells, which is inherently difficult to do without perturbing the latent state of the cells. With current approaches, cellular activation is required to enumerate latent cells, which disrupts the very state that we would like to study. To overcome this major roadblock to latency studies, we have developed an HIV-induced lineage tracing model (HILT) in humanized mice that irreversibly genetically marks infected cells. When combined with single cell RNA sequencing (scRNAseq) approaches in HIV-infected, ART-treated animals, the result is an emerging genomic resolution view of transcriptional states associated with HIV infection and latency.

Preliminary studies presented here begin to provide an unprecedented, single cell genomic classification of HIV-infected CD4 T cell lineages and states during acute infection and during early antiretroviral treatment. In this proposal, we explore single cell multi-omics of persistently infected human CD4 T cells in humanized mice and examine how it responds to oligoclonal TCR activation versus homeostatic proliferation. The systems biology of T cells will be used to dissect latent reservoirs in novel small animal models for HIV to understand how a reservoir is generated and maintained in distinct cell states. Genomic analysis may be used to identify drugs or biologic interventions that can push cells towards active HIV expression and are independent of cellular activation state. These could be used to develop cure strategies aimed at enhancing expression and the progressive decay of the latent reservoir.

We hypothesize that a single cell multi-omics approach will elucidate developmentally diverse T cell lineages and transcriptional states that harbor HIV reservoirs, and that each cluster may display unique gene programs associated with HIV persistence. Reversing the expression of factors associated with HIV persistence may reactivate the reservoir. Single cell multi-omics may unveil new targeted strategies to purge HIV from different T cell states. The proposed study leverages a team with expertise in HIV immunopathogenesis, humanized mice, single cell genomics, to deeply phenotype human T cell reservoirs in novel small animal models.

Icahn School Of Medicine At Mount Sinai

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York, New York 100296504 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 429% from $630,219 to $3,331,655.