Naive T cells are dispensable for memory CD4⁺ T cell homeostasis in progressive simian immunodeficiency virus infection

The development of AIDS in chronic HIV/simian immunodeficiency virus (SIV) infection has been closely linked to progressive failure of CD4⁺ memory T cell (T_M) homeostasis. CD4+ naive T cells (T_N) also decline in these infections, but their contribution to disease progression is less clear. We assessed the role of CD4⁺ T_N in SIV pathogenesis using rhesus macaques (RM_s) selectively and permanently depleted of CD4⁺ T_N before SIV infection. CD4⁺ T_N-depleted and CD4⁺ T_N-repleted RMs were created by subjecting juvenile RMs to thymectomy versus sham surgery, respectively, followed by total CD4⁺ T cell depletion and recovery from this depletion. Although thymectomized and sham-treated RMs manifested comparable CD4⁺ T_M recovery, only sham-treated RMs reconstituted CD4⁺ T_N. CD4⁺ T_N-depleted RMs responded to SIVmac239 infection with markedly attenuated SIV-specific CD4⁺ T cell responses, delayed SIVenv-specific Ab responses, and reduced SIV-specific CD8⁺ T cell responses. However, CD4⁺ T_N-depleted and -repleted groups showed similar levels of SIV replication. Moreover, CD4⁺ T_N deficiency had no significant effect on CD4⁺ T_M homeostasis (either on or off anti-retroviral therapy) or disease progression. These data demonstrate that the CD4⁺ T_N compartment is dispensable for CD4⁺ T_M homeostasis in progressive SIV infection, and they confirm that CD4⁺ T_M comprise a homeostatically independent compartment that is intrinsically capable of self-renewal.