THE EXPRESSION OF FUNCTIONAL VPX DURING PATHOGENIC SIVmac INFECTIONS OF RHESUS MACAQUES SUPPRESSES SAMHD1 IN CD4+ MEMORY T CELLS. Primate lentiviruses such as HIV and its SIV simian relative encode accessory proteins that suppress cellular restriction factors interfering with efficient replication. One of these, designated Vpx, is produced in infected cells by HIV 2 and some SIV strains, which cause endemic infections in African monkeys. The primary function of Vpx has long been thought to facilitate infectivity in dendritic cells and macrophage by degrading the Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1), which restricts virus replication in these cells. We show that when macaques were inoculated with SIV carrying the Q76A Vpx point mutation, which specifically affects the interaction of Vpx with DCAF1 and the subsequent recruitment of SAMHD1 for degradation, virus acquisition, progeny virion production in memory CD4+ T lymphocytes during the acute infection, and the maintenance of set point viremia were greatly attenuated. Revertant viruses, which emerged in two infected animals, carried substitutions located in likely contact points of Vpx with the c-terminal domain of DCAF1. Thus our data indicate that contrary to the commonly held belief that the principal function of SIV Vpx is to facilitate virus replication in myeloid lineage cells, the need to degrade endogenous SAMHD1 during SIV infections of memory CD4+ T cells in vivo is critically important and drives the selection for Vpx revertant viruses, capable of mediating the degradation of SAMHD1 and generating high levels of plasma viremia. QUALITY AND QUANTITY OF TFH CELLS ARE CRITICAL FOR BROAD ANTIBODY DEVELOPMENT IN SHIVAD8 INFECTION. Most anti-HIV-1 broadly neutralizing antibodies (bNAbs) show a high degree of somatic hypermutation (SHM), suggesting that they have undergone extensive affinity maturation within germinal centers (GCs). It is known that T follicular helper (TFH) cells are needed to promote affinity maturation of B cells during an immune response; however, the role of TFH during HIV-1 infection is undefined within lymph node germinal centers (GCs). Rhesus macaques were used to investigate the relationship in the early stage of chronic SHIVAD8 (simian-human immunodeficiency virus AD8) infection between envelope (Env)specific TFH cells, Env-specific B cells, virus, and the generation of bNAbs during later infection. We found that both the frequency and quality of Env-specific TFH cells were associated with an expansion of Env-specific immunoglobulin Gpositive GC B cells and broader neutralization across HIV clades. We also found a correlation between breadth of neutralization and the degree of somatic hypermutation in Env-specific memory B cells. High viral loads and greater diversity of Env sequences were observed in macaques that developed cross-reactive neutralization as compared to those that did not. These studies highlight the importance of boosting high-quality TFH populations as part of a robust vaccine regimen aimed at eliciting bNabs.
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