Macrophages(M?) are important drivers of HIV pathogenesis and progression to AIDS. The significance of M? infection in viremic individuals is well established, in contrast to the role of M? in suppressed HIV infection. Contribution of the M? reservoir to viral reactivation and rebound upon analytical treatment interruption(ATI) of antiretroviral therapy(ART) has not been determined. Using an SIV/rhesus macaque model of HIV, we sought to determine whether depleting CD4 T cells from blood and tissue altered the contribution of the M? reservoir to viral rebound.
In the SIVmac251 model, we assessed the effect of CD4 depletion on M? reservoirs in blood, spleen, bronchoalveolar lavage(BAL) and brain. Three groups were assessed(n=18). All animals began ART treatment at 14 days post infection(dpi), and continued until 280dpi, the terminal timepoint for the ART group. At 280dpi the ATI group was withdrawn from ART. At 210dpi, the CD4dep+ATI group was given an anti-CD4 antibody(CD4R1) intravenously to deplete CD4 T cells from blood and tissue. At 280dpi this group was also withdrawn from ART for ATI. Terminal time points for both ATI groups were determined when plasma viral rebound reached set-point. To assess the M? latent reservoir, we utilized the IPDA and M?-QVOA.
All animals had similar acute viral loads and suppressed within 40 days of ART initiation. We observed significant CD4 depletion in the blood(95%), lymph nodes(70%) and spleen(50%) post CD4R1 administration, which was maintained throughout ATI. No difference was observed in time-to or set-point of viral rebound in the plasma in the ATI groups. In contrast, only 1/6 animals in the ATI group rebounded in CSF compared to all 6/6 animals in CD4dep+ATI group. We observed no change in the intact DNA reservoir in M? isolated from blood, spleen and BAL. However, there was a significant increase in the reactivatable reservoir in M?-rich tissues (brain and BAL) in CD4dep+ATI compared to ATI and ART groups. In contrast, M? isolated from CD4-rich tissues (blood and spleen) had smaller reactivatable reservoirs.
Our data demonstrate that CD4 depletion prior to ATI does not reduce the viral reservoir and enhances reactivation of latently-infected M?. Our model closely mimics what is observed in late-stage infection, as CD4 T cells are depleted, and infected M? become the principal reservoir driving viremia. This work has implications for cure, as eliminating CD4 T cells could result in severe disease outcomes post ATI.