Probes for HIV-1

CD4+ T cells are the primary HIV-1 target cell, with the vast majority of these cells residing within lymphoid tissue compartments throughout the body. Predictably, HIV-1 infection, replication, localization, reservoir establishment and persistence, as well as associated host immune and inflammatory responses and disease pathology principally take place within the tissues of the immune system. By virture of the fact that the virus-host struggle is played out within lymphoid and additional tissues compartments in HIV-1 infected individuals it is critical to understand HIV-1 infection and disease within these relevant tissue sites; however, there are obvious limitations to studying these dynamic processes in humans. Nonhuman primate (NHP) research has provided a vital bridge between basic and preclinical research and clinical studies, with experimental SIV infection of NHP models offering unique opportunities to understand key processes of HIV-1 infection and disease that are either not practically feasible or ethical in HIV-1 infected humans. In this review we will discuss current approaches to studying the tissue based immunopathogenesis of AIDS virus infection in NHPs, including both analyses of tissues obtained at biopsy or necropsy and complementary non-invasive imaging approaches that may have practical utility in monitoring HIV-1 disease in the clinical setting.

A safe and effective human immunodeficiency virus type 1 (HIV-1) vaccine is urgently needed, but remains elusive. While HIV-1 live-attenuated vaccine can provide potent protection as demonstrated in rhesus macaque-simian immunodeficiency virus model, the potential pathogenic consequences associated with the uncontrolled virus replication preclude such vaccine from clinical applications. We investigated a novel approach to address this problem by controlling live-attenuated HIV-1 replication through an unnatural genetic switch that was based on the amber suppression strategy. Here we report the construction of all-in-one live-attenuated HIV-1 mutants that contain genomic copy of the amber suppression system. This genetic modification resulted in viruses that were capable of multicycle replication in vitro and could be switched on and off using an unnatural amino acid as the cue. This stand-alone, replication-controllable attenuated HIV-1 virus represents an important step toward the generation of a safe and efficacious live-attenuated HIV-1 vaccine. The strategy reported in this work can be adopted for the development of other live-attenuated vaccines.

Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals but does not eliminate the reservoir of latently infected cells. Recent work identified PD-1+ follicular helper T (Tfh) cells as an important cellular compartment for viral persistence. Here, using ART-treated, SIV-infected rhesus macaques, we show that CTLA-4+PD-1- memory CD4+ T cells, which share phenotypic markers with regulatory T cells, were enriched in SIV DNA in blood, lymph nodes (LN), spleen, and gut, and contained replication-competent and infectious virus. In contrast to PD-1+ Tfh cells, SIV-enriched CTLA-4+PD-1- CD4+ T cells were found outside the B cell follicle of the LN, predicted the size of the persistent viral reservoir during ART, and significantly increased their contribution to the SIV reservoir with prolonged ART-mediated viral suppression. We have shown that CTLA-4+PD-1- memory CD4+ T cells are a previously unrecognized component of the SIV and HIV reservoir that should be therapeutically targeted for a functional HIV-1 cure.