B LYMPHOCYTES, BUT NOT DENDRITIC CELLS, EFFICIENTLY HIV-1 TRANS-INFECT NAÏVE CD4+ T CELLS: IMPLICATIONS FOR THE VIRAL RESERVOIR

Abstract

Insight into the establishment and maintenance of HIV-1 infection in resting CD4+ T cell subsets is critical for the development of therapeutics targeting the HIV-1 reservoir. Although the frequency of HIV-1 infection, as quantified by the frequency of HIV-1 DNA, is lower in CD4+ naive T cells (TN) compared to the memory T cell subsets, recent studies have shown that TN cells harbor a large pool of replication-competent virus. Interestingly, however, TN cells are highly resistant to direct (cis) HIV-1 infection in vitro, in particular to R5-tropic HIV-1, as TN cells do not express CCR5. In this study, we investigated whether TN cells could be efficiently HIV-1 trans-infected by professional antigen-presenting B lymphocytes and myeloid dendritic cells (DC) in the absence of global T cell activation. We found that B cells, but not DC, have a unique ability to efficiently trans infect TN cells in vitro. In contrast, both B cells and DC mediated HIV-1 trans infection of memory and activated CD4+ T cells. Moreover, we found that TN isolated from HIV-1-infected nonprogressors (NP) harbor significantly disproportionately lower levels of HIV-1 DNA compared to TN isolated from progressors. This is consistent with our previous finding that APC derived from NP do not efficiently trans-infect CD4+ T cells due to alterations in APC cholesterol metabolism and cell membrane lipid raft organization. These findings support that B cell-mediated trans infection of TN cells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. ImportanceThe latent human immunodeficiency virus type 1 (HIV-1) reservoir in persons on antiretroviral therapy represents a major barrier to a cure. Although most studies have focused on the HIV-1 reservoir in the memory T cell subset, replication competent HIV-1 has been isolated from naive T cells, and CCR5-tropic HIV-1 has been recovered from CCR5negTN cells from ART-suppressed HIV-1-infected individuals. In this study, we showed that CCR5negTN cells are efficiently trans infected with R-5 tropic HIV-1 by B lymphocytes, but not by myeloid dendritic cells. Furthermore, we found that TN isolated from NP harbor no or significantly less copies of HIV-1 DNA compared to ART-suppressed progressors. These findings support that B cell-mediated trans infection of TN cells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. Understanding the establishment and maintenance of the HIV-1 latent reservoir is fundamental for the design of effective treatments for viral eradication.