Long-term Antiretroviral Treatment Initiated in Primary HIV-1 Infection Affects the Size, Composition and Decay Kinetics of the Reservoir of HIV-1 Infected CD4 T Cells

Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therapy in primary HIV-1 infection and remained on suppressive treatment for >10 years; patients with similar treatment duration but initiation of therapy in chronic HIV-1 infection served as controls. We observed that independently of the timing of treatment initiation, HIV-1 DNA in CD4 T cells decayed exclusively during the initial 3-4 years of treatment; however, in patients who started antiretroviral therapy in acute infection, this decay occurred faster and was more pronounced, leading to substantially lower levels of cell-associated HIV-1 DNA after long-term treatment. Despite this smaller size, the viral CD4 T cell reservoir in persons with early treatment initiation consisted more dominantly of the long-lasting central-memory and T memory stem cells. Moreover, gene transcripts in CD4 T cells associated with the total viral CD4 T cell reservoir size frequently correlated with the relative proportion of these long-lived CD4 T cell subsets, suggesting shared gene expression signatures for maintaining HIV-1 persistence and preservation of long-lasting CD4 T cell subsets. Despite effective suppression of viral antigens for >10 years, HIV-1-specific T cell responses remained continuously detectable in both study groups. Together, these data suggest that although early HIV-1 treatment initiation, even when continued for >10 years, is unlikely to lead to viral eradication, the presence of low viral reservoirs and durable HIV-1 T cell responses may make such patients attractive candidates for future interventional studies aiming at HIV-1 eradication and cure. We used Dynabeads Untouched Human CD4 T Cells kit (Invitrogen) for CD4 isolation from a median of 10 million PBMCs. RNA was extracted from CD4+ T cells using the mirVana miRNA Isolation Kit, Ambion. whole genome transcriptional profiling was performed using WG-DASL microarrays (Illumina) according to standard protocols. We included an cohort of elite controllers (n =10 ), patients long term HAART treated after the chronic phase of the infection (n=10) and patients long term HAART treated after the acute phase of the infection (n=8).