It is well-established that defective HIV proviruses accumulate rapidly during acute HIV infection and constitute more than ninety percent of all proviruses in people living with HIV, regardless of the timing of antiretroviral therapy (ART) initiation. Moreover, recent evidence suggests that the defective HIV reservoir does not decay over time, even after decades of ART administration, and expresses both viral RNAs and proteins in people living with HIV on ART with currently underexplored and/or unknown consequences. It is possible that HIV RNA and protein expression from defective proviruses contribute to chronic immune activation and the subsequent development of related comorbidities in people living with HIV. Additionally, HIV protein expression from defective proviruses could produce irrelevant ‘decoy’ epitopes that distract and exhaust the immune system, affecting its ability to control intact virus replication and rebound upon cessation of ART and/or clear infected cells, potentially leading to differences in rates of post-treatment control or outcomes of viral eradication strategies. Likewise, HIV Env expression from defective proviruses could interfere with therapeutic broadly neutralizing antibody (bNAb)-mediated control of viral replication or rebound following a treatment interruption. Finally, defective proviruses could affect HIV reservoir dynamics by influencing reservoir clonal proliferation. Therefore, the focus of this notice of funding opportunity (NOFO) is to resolve key questions regarding defective HIV reservoirs impact on 1) viral pathogenesis and antiviral immune responses on ART, 2) viral persistence, dynamics, and post-treatment control, and/or 3) responses to HIV cure strategies.
Assays used to quantify HIV viral loads determine viral sensitivities to bNAbs, or screen proviruses for known ART resistance mutations, do not exclude defective proviruses from analysis. Including defective proviruses in those assays can skew the interpretation of results and have important clinical implications. For example, a potential participant in an HIV bNAb efficacy clinical trial might be excluded from participation if their highly abundant, defective HIV reservoir sequences indicate potential resistance to the bNAb being tested, despite the fact that their far less abundant, but more relevant, intact HIV reservoir sequences might be fully sensitive to the bNAb.
Accordingly, this NOFO also supports methods development and assay optimization to exclude defective proviruses from analyses to increase the accuracy and utility of crucial clinical assays.
Research Objectives and Scope
This NOFO encourages the characterization of the defective HIV proviral landscape in blood and tissue sites in people living with HIV on ART, the quantification of HIV RNA and protein expression from defective proviruses in vivo, and identification of defective proviral epitopes that drive autologous anti-HIV immune responses. The effects of the defective proviruses on HIV pathogenesis, reservoir dynamics, mechanisms of persistence, post-treatment control, and/or cure strategies will be supported. Methods development will also be supported to optimize viral load measurement, bNAb sensitivity testing, and drug-resistance screening assays to exclude the impact of defective proviruses from those assays. Expertise may be needed in virology, immunology, single-cell multiomics, transcriptomics/proteomics, RNA-Seq, RNA splicing, epitope mapping, HIV reservoir quantification, or technical HIV clinical assay development.
The scope of the research will include basic research, methods development and validation, and the analysis of longitudinal blood and tissue samples from preclinical and clinical studies of people living with HIV and relevant animal models. Clinical trials are not allowed, but human samples are required. The use of samples from clinical trials supported by other funding mechanisms or samples collected from observational studies are encouraged. The use of SIV/SHIV virus models is not considered in scope because of the differences in ratios of defective: intact SIV/SHIV proviruses in primate models vs. in HIV models; applications may only include HIV.
For more information, please see the opportunity website.