Activated memory CD4⁺ T helper cells repopulate the intestine early following antiretroviral therapy of simian immunodeficiency virus-infected rhesus macaques but exhibit a decreased potential to produce interleukin-2

Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model, we performed a longitudinal study to determine the effect of antiretroviral therapy on the phenotype and functional potential of CD4⁺ T cells repopulating intestinal mucosa in human immunodeficiency virus infection. Severe depletion of CD4⁺ and CD4⁺ CD8⁺ T cells occurred in the intestinal mucosa during primary SIV infection. The majority of these cells were of activated memory phenotype. Phosphonate 9-[2- (phosphomethoxypropyl]adenine (PMPA) treatment led to a moderate suppression of intestinal vital loads and repopulation of intestinal mucosa by predominantly activated memory CD4⁺ T-helper cells. This repopulation was independent of the level of viral suppression. Compared to preinfection values, the frequency of naive CD4⁺ T cells increased following PMPA therapy, suggesting that new CD4⁺ T cells were repopulating the intestinal mucosa. Repopulation by CD4⁺ CD8⁺ T cells was not observed in either jejunum or colon lamina propria. The majority of CD4⁺ T cells repopulating the intestinal mucosa following PMPA therapy were CD29(hi) and CD11a(hi). A subset of repopulating intestinal CD4⁺ T cells expressed Ki-67 antigen, indicating that local proliferation may play a role in the repopulation process. Although the majority of repopulating CD4⁺ T cells in the intestinal mucosa were functionally capable of providing B- and T-cell help, as evidenced by their expression of CD28, these CD4⁺ T cells were found to have a reduced capacity to produce interleukin-2 (IL-2) compared to the potential of CD4⁺ T cells prior to SIV infection. Persistent viral infection may play a role in suppressing the potential of repopulating CD4⁺ T cells to produce IL-2. Hence, successful antiretroviral therapy should aim at complete suppression of viral loads in mucosal lymphoid tissues, such as intestinal mucosa.