HIV-Specific CD4+ T Cells May Contribute to Viral Persistence in HIV Controllers

Background. Human immunodeficiency virus (HIV)-infected individuals maintaining plasma HIV RNA levels <75 copies/mL in the absence of therapy (HIV controllers'') often maintain high HIV-specific T cell responses, which likely contribute to the control of viral replication. Despite robust immune responses, these individuals never eradicate HIV infection. We hypothesized that HIV-specific CD4(+) T cells might serve as target cells for HIV, contributing to viral persistence in this setting. Methods. We measured frequencies of activated (CD38(+) HLA-DR+) and HIV Gag-specific CD4(+) and CD8(+) T cells and plasma-and cell-associated levels of HIV RNA and DNA in a cohort of 38 HIV controllers. Results. Although there was no evidence of a relationship between the extent of low-level viremia and the frequency of either activated or HIV-specific CD4(+) T cells, controllers with higher HIV-specific CD4(+) T cell frequencies had higher cell-associated HIV DNA levels (rho = 0.53; P = .019). Higher activated CD4(+) T cell frequencies were also associated with higher levels of cell-associated DNA (P = .027) and RNA (P = .0096). However, there was no evidence of a relationship between cell-associated HIV RNA or DNA levels and HIV-specific CD8(+) T cell frequencies. Conclusions. These data support a model in which strong HIV-specific CD4(+) T cell responses in HIV controllers, while contributing to a potent adaptive immune response, may also contribute to viral persistence, preventing the natural eradication of HIV infection.