Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

Some rare HIV-1-infected individuals, referred to as HIV controllers (HIC), have persistently undetectable plasma viral load in the absence of therapy. This control of HIV-1 replication has been associated with a strong, multifunctional specific CD8 ؉ T cell response. However, no direct link between this immune response and the control of viremia has so far been provided. We investigated parameters of specific CD8 ؉ T cell response and in vitro susceptibility to HIV-1 infection in 11 HIC. We found high frequencies of HIV-specific CD8 ؉ T cells. Interestingly, these cells expressed the activation marker HLA-DR but not CD38. This unique phenotype differentiates HIV-specific CD8 ؉ T cells from HIC and noncontroller subjects and likely reflects a high potential to expand upon exposure to antigen and a capacity to exert effector functions. Accordingly, although CD4 ؉ T cells from HIC were fully susceptible to HIV-1 superinfection, their CD8 ؉ T cells effectively suppressed HIV-1 infection. Remarkably, this potent anti-HIV activity was observed without prior stimulation of CD8 ؉ T cells. This activity was not mediated by secreted inhibitory factors but was due to the elimination of infected CD4 ؉ T cells and was observed only with autologous CD4 ؉ T cells, indicating an HLA-restricted cytotoxic mechanism. This constitutive antiviral capacity of CD8 ؉ T cells could account for the control of viral replication in HIC.HIV suppression ͉ CD8 ϩ T cells ͉ HLA-DR ͉ CD38

We identified a total 15 patients who have maintained undetectable plasma HIV RNA loads without antiretroviral treatment for >10 years from cohorts of 1300 and 1551 patients infected with human immunodeficiency virus (HIV). These 15 patients, whom we have referred to as "HIV controllers," are characterized by a low HIV DNA load in peripheral blood mononuclear cells and by a strong HIV-specific immune response.