Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study

Abstract

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.

Author Summary

There is a renewed scientific interest in developing strategies allowing long-term remission in HIV-1-infected individuals. Very rare (<1%) patients are able to spontaneously control viremia to undetectable levels (HIV controllers, HICs). However, the possibility to translate their mechanisms of control to other patients is uncertain. Starting antiretroviral therapy during primary infection may provide significant benefits to HIV-infected patients (i.e. reduction of viral reservoirs, preservation of immune responses, protection from chronic immune activation). Indeed, we have observed that some HIV-infected patients interrupting a prolonged antiretroviral therapy initiated close to primary infection are able to control viremia afterwards. We present here 14 of such post-treatment controllers (PTCs). We show that PTCs have achieved control of infection through mechanisms that are, at least in part, different from those commonly observed in HICs and that their capacity to control is likely related to early therapeutic intervention. We found that PTCs were able, after therapy interruption, to keep, and in some cases further reduce, a weak viral reservoir. This might be related to the low contribution of long-lived cells to the HIV-reservoir in these patients. Finally, we estimated the probability of maintaining viral control at 24 months post-early treatment interruption to be ∼15%, which is much higher than the one expected for spontaneous control.