Reduced HIV-1 latent reservoir outgrowth and distinct immune correlates among women in Rakai, Uganda

Addressing an HIV cure in LMIC

“…The most well-characterized clinical measure that correlates with reservoir size is pre-ART viral load (VL). Several studies show that pre-ART VL setpoint, or even just the VL the time of ART initiation, correlates positively with HIV-1 DNA [ 13 , 127 ] and QVOA estimates of reservoir size [ 8 , 9 ], which is consistent with studies showing that early ART restricts reservoir size (both replication-competent and HIV-1 DNA) [ 91 , 129 – 131 ]. In ART-treated patients, CD4 counts over time have also been shown to predict replication-competent reservoir size in PLWH who initiated treatment in acute infection [ 132 ], and several studies have identified the extent of CD4 depletion as shaping the HIV-1 DNA proviral load [ 133 , 134 ], with nadir CD4 count and CD4:CD8 ratio shown to be strong negative correlates of reservoir size.…”

“…However, we have previously reported that PLWH in Uganda (who initiated ART during chronic infection) have reduced replication competent reservoir size (three-fold lower by QVOA) compared to North Americans [ 8 ], and that Ugandan females have additionally smaller replication-competent reservoirs than males. Interestingly, despite lower QVOA outgrowth, HIV-1 DNA levels were similar between males and females [ 9 ]. Other studies report lower intracellular HIV-1 DNA in females compared to males [ 64 , 65 ], highlighting important differences that may need to be considered when assessing latency reversal strategies.…”

“…In ART-treated patients, CD4 counts over time have also been shown to predict replication-competent reservoir size in PLWH who initiated treatment in acute infection [ 132 ], and several studies have identified the extent of CD4 depletion as shaping the HIV-1 DNA proviral load [ 133 , 134 ], with nadir CD4 count and CD4:CD8 ratio shown to be strong negative correlates of reservoir size. Furthermore, time on ART has also been shown to correlate negatively with replication-competent reservoir size [ 9 ].…”

“…Since immune activation and inflammation are known to differ between the sexes, detailed studies into the immune correlates of reservoir size in males and females are needed. We recently reported a difference in the immune correlates between males and females in PLWH in Uganda [ 9 ]. While in males the frequency of PD-1 + CD4 + T cells and IL-2 + CD8 + T cells were positive and negative correlates of replication-competent reservoir size, respectively, only TNF + CD8 + T cells was found to have a positive association with replication-competent reservoir size in females.…”

“…In-human trials (passive immunization) have been conducted with several bNAbs and they have been shown to be tolerable and safe, even at high doses and when administered repeatedly in both HIV-1 uninfected [ 4 , 5 ] and infected adults [ 6 , 7 ]. Monoclonal bNAb therapy did not result in decrease in residual plasma viraemia [ 8 ], HIV-1 DNA/RNA [ 8 , 9 ] or outgrowth viruses (demonstrated with VRC01) [ 8 ] but did result in a delay in viral rebound after analytical treatment interruption (ATI), demonstrated with VRC01 [ 10 , 11 ], 3BNC117 [ 12 ], and UB-241 [ 13 ], although results were highly variable across trials (ranging from 4 to 16 weeks median time to rebound). Combination bNAb therapy has also shown promise, with the benefit of a decreased likelihood of developing resistance to multiple antibodies [ 7 ].…”