Background:  Rapid and massive depletion of memory CD4⁺CCR5⁺ cells in the gut-associated lymphoid tissue (GALT) in acute infection is a hallmark of HIV and simian immunodeficiency virus (SIV) pathogenesis. However, it is not known whether long-term non-progressors (LTNP) experience the same rapid and profound loss of gut CD4⁺ cells in the acute infection. We have used LTNP SIV-infected rhesus macaques as a model to test the dynamics of memory CD4⁺CCR5⁺ cells in GALT.

Methods:  We used 12 SIV-infected Chinese-origin rhesus macaques. Blood, lymph node, and intestinal biopsies were sampled before and post infection. CD8⁺ cell depletion was performed using anti-CD8 monoclonal antibody in 2 of 4 LTNP. Expression of T cell, naive and memory, activation and SIV co-receptor markers were measured by flow cytometry.

Results:  Of 12 monkeys, 8 developed AIDS between 6 and 25 months after infection (progressors); 4 were LTNP and remained healthy with undetectable plasma viral loads. Memory CD4⁺CCR5⁺ cells were profoundly depleted at days 11 to 28 post infection in all 12 monkeys. The ability to restore memory CD4⁺CCR5⁺ cells was defined as the percentage of these cells post infection, compared to baseline levels. In progressors, all lacked the ability to maintain restoration of memory CD4⁺CCR5⁺ cells. In the LTNP, variable memory cell recovery began at day 60 post infection and all had restored 15% or more of baseline levels by day 180 and maintained this level or increased it. In 2 of 4 LNTP (AJ07 and V542), in vivo CD8⁺ depletion was done to test the role of CD8 cells in LTNP on memory CCR5⁺ cell restoration. AIDS was induced in 1 (V542) at day 35 post anti-CD8 treatment, the other (AJ07) remains healthy. Viremia returned but then declined. The rate of mucosal restoration of memory CD4⁺CCR5⁺ cells was 1.8-fold faster in AJ07 than V542. Treatment with anti-CD8 monoclonal antibody greatly reduced gut CD8⁺ cells from 70% to 0.5% in AJ07 and from 60% to 0.1% in V542 at day 9. By day 35, AJ07 had restored CD8⁺ cells to 79.9%, V542 had only 39.6%, suggesting that a rapid rate of CD8 cell recovery was necessary to return to the LTNP state.

Conclusions:  Profound depletion of memory CD4⁺CCR5⁺ cells in GALT was indistinguishable between disease progressors and LTNP at the acute stage of infection. Restoration of mucosal memory CD4⁺CCR5⁺ cells during the chronic phase predicted LTNP. Sufficient CD8⁺ T cells may be essential for controlling SIV infection in GALT and required for restoration of memory CD4⁺CCR5⁺ T cells.