Increased numbers of intact HIV sequences in a4b7 T cells during acute seroconversion

Background: Memory CD4 T cells expressing the integrin α4β7 seem highly susceptible to HIV-1 infection, and may represent a preferential site for viral infection and reservoir establishment. Recent studies suggested that when used in combination with regular antiretroviral therapy during acute SIV infection, monoclonal antibodies blocking α4β7 may enable rhesus macaques to control viremia after ART discontinuation. In contrast, a clinical trial with α4β7 blocking antibodies in humans with chronic HIV-1 infection has recently been completed, without markedly increased frequencies of individuals achieving post-treatment control. Methods: PBMCs were isolated from HIV-1 positive patients (n=4) during acute seroconversion before ART initiation (Fiebig stage III-V). CD4 T cells were enriched by negative MACS selection, and the α4β7-positive and β7-negative memory CD4 T cell populations were sorted by FACS. Near full length, single-genome HIV-1 DNA sequencing of total CD4 T cells, β7-positive and β7-negative CD4 T cell subsets was performed, as described previously. Phylogenetic associations were determined using sequence alignments by MUSCLE and tree building by Unweighted Pair Group Method with Arithmetic Mean (UPGMA). Results: In three out of four patients analyzed at acute seroconversion, the number of HIV-1 DNA copies (intact and defective combined) was higher in the β7-positive cells compared to β7-negative and total CD4+ T cells (mean of 897, 186 and 117 total HIV-1 copies/million cells, respectively). The frequency of intact HIV-1 proviruses was also highest in the []7-positive compartment relative to the other two cell populations (mean of 558 versus 99 and 72 intact HIV copies/million cells, respectively). The patient without an HIV-1 enrichment in the β7-positive subset presented with a very high peak viral load (> 7 log copies/mL), low CD4 nadir count below 100 cells/mm3 and CD4 T cells skewed towards a memory phenotype. Phylogenetic analysis of the intact proviral sequences showed that these viruses intermingle between the three different subsets and suggests absence of compartmentalization within the analyzed cell populations. Conclusions: This study suggests that α4β7 memory CD4 T cells represent a primary target site for viral replication during the earliest stages of HIV-1 infection, and raise the possibility that administration of α4β7 antibodies during acute HIV-1 infection may reduce viral reservoir establishment