Identification and description of all cellular reservoirs of persistent HIV infection is of crucial importance to HIV eradication efforts. There is increasing evidence of the existence of additional latent reservoirs in the peripheral blood, and also within the tissue where a substantial fraction of the total lymphocytes of the body are located. We have discovered that a subclass of ?? T cells that express the V?2 TCR chain, harbor latent but replication-competent HIV. Furthermore, we have described a mechanism to explain V?2 cell infection, showing that although these cells generally express extremely low levels of the CD4 receptor, they can upregulate the CD4 receptor following stimuli in vitro. We have confirmed this finding by the discovery that acutely HIV-infected patients studied less than three weeks after infection, are found to have substantial expression of the CD4 receptor on V?2 cells. We propose to validate and clarify the importance of this new latent HIV reservoir within ?? T cells by i) extending our studies to include the complementary V?1 TCR ?? T cell population, as we find significant levels of HIV DNA within this second ?? T cell population, ii) studying infection and latency within ?? T cells in the gut associated lymphoid tissue (GALT), lymphoid tissues (LT) and liver, given the predominance of ?? T cells within these tissues, iii) analyze the stability and durability of latency within the ?? T cell reservoir, and iv) explore therapeutic approaches to disrupt latency within ?? T cells. Our investigations will contribute critically to the effort to define and eradicate HIV infection within all persistent, latently infected cells.
The major barrier towards efforts to cure HIV infection is the existence of viral reservoirs that persist despite antiretroviral therapy. Most current efforts to eradicate HIV infection rely on the development of agents capable of inducing expression of quiescent HIV without enhancing new infection, and the provision of a potent immune response to clear reactivated HIV. To date most studies have focused on reactivation and clearance of HIV in resting memory CD4+ T cells shown to contain the largest proportion of the latent, quiescent viral reservoir. However, this strategy will be incomplete if additional cells that can act as reservoirs of latent HIV infection are not targeted. We will study ?? T cells, an unexpected and novel latent HIV reservoir that we have recently defined, in HIV-infected patients on suppressive therapy in both peripheral blood and in tissue, to fully understand this new site of persistent HIV infection, and to define therapeutic requirements for its elimination.
