Gut associated lymphoid tissue (GALT) is depleted of most CD4 cells early after HIV infection and does notreconstitute with antiretroviral therapy (ARV), yet few clinical problems are reported in this population withaltered gut immunity. Importantly, recent studies have documented increasing rectal neoplasia from thechronic, latent mucosal pathogen human papilloma virus (HPV). In our preliminary data we document themassive depletion of CD4+ T cells from lamina propria (LP) and show that effector cells populating the LP donot recover with ARV. However, we do show the central memory (CM) population of GALT has potential forreconstitution with ARV. In addition we have found the frequency of HIV DNA+ cells in GALT continues toincrease after ARV initiation and in Projects 1 and 2 we document frequent detection of HIV episomes.These observations suggest a model of ongoing cryptic replication of HIV in GALT of ARV treated individualsthat leads to a gradual depletion of the CM population, which, in turn, eventually manifests as clinicaldisease. This model is in agreement with recent observations in SIV infected non-human primates where thesize of the CM population predicted disease progression and survival. We therefore hypothesize thatcryptic HIV replication and the subsequent depletion of CD4 cells undermines immune function ingut associated lymphoid tissue (GALT). To investigate this hypothesis we will study the degree to whichcryptic replication of HIV in GALT determines the natural history of two common, chronic, latent mucosalinfections with frequent rectal reactivation (i.e., herpes simplex type 2 [HSV2] and cytomegalovirus [CMV]).We will measure the frequency of HIV episomes in CD4 subsets (especially the CM subset) in GALT, LN,and PB, the frequency of HSV2 and CMV specific CD4 and CDS T cells in each compartment, and thefrequency of rectal reactivation of HSV2 and CMV. We will determine the relationship between the frequencyof cryptic HIV replication to the size of the CM in PP and effector memory (EM) population in LP and theability of the immune system to control reactivation of HSV2 and CMV. We believe completion of thesestudies will provide a more complete understanding of HIV pathogenesis which will translate into targetedtherapies to improve GALT immune function.
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