Addressing an HIV cure in LMIC

Abstract

HIV-1 persists in infected individuals despite years of antiretroviral therapy (ART), due to the formation of a stable and long-lived latent viral reservoir. Early ART can reduce the latent reservoir and is associated with post-treatment control in people living with HIV (PLWH). However, even in post-treatment controllers, ART cessation after a period of time inevitably results in rebound of plasma viraemia, thus lifelong treatment for viral suppression is indicated. Due to the difficulties of sustained life-long treatment in the millions of PLWH worldwide, a cure is undeniably necessary. This requires an in-depth understanding of reservoir formation and dynamics. Differences exist in treatment guidelines and accessibility to treatment as well as social stigma between low- and-middle income countries (LMICs) and high-income countries. In addition, demographic differences exist in PLWH from different geographical regions such as infecting viral subtype and host genetics, which can contribute to differences in the viral reservoir between different populations. Here, we review topics relevant to HIV-1 cure research in LMICs, with a focus on sub-Saharan Africa, the region of the world bearing the greatest burden of HIV-1. We present a summary of ART in LMICs, highlighting challenges that may be experienced in implementing a HIV-1 cure therapeutic. Furthermore, we discuss current research on the HIV-1 latent reservoir in different populations, highlighting research in LMIC and gaps in the research that may facilitate a global cure. Finally, we discuss current experimental cure strategies in the context of their potential application in LMICs.

Reduced and highly diverse peripheral HIV-1 reservoir in virally suppressed patients infected with non-B HIV-1 strains in Uganda

“…A number of different methodologies for HIV-1 reservoir quantification have been developed over the last two decades [ 15 , 19 , 58 ], although there is no clear correlation among most assays used to quantify latently HIV-infected cells [ 26 ]. The main challenge for all these cell-based and/or molecular assays has been the very limited number of latently HIV-infected cells potentially harboring replication-competent virus [ 3 , 8 ]. Cell (culture)-based methods such as Q-VOA [ 20 ], TILDA [ 29 ], and ultrasensitive p24 ELISAs measure replication-competent viruses but can be labor intensive and might under or overestimate the size of the HIV-1 reservoir [ 15 ].…”

“…While our general knowledge of the HIV-1 latent reservoir, and potential cure strategies, has been mostly associated with subtype B HIV-1 infections [ 3 , 8 ], a limited number of studies have analyzed the HIV-1 reservoir in individuals infected with non-B viruses. Similar to our findings, Prodger et al [ 45 ] used Q-VOA to show that virally suppressed Ugandans had a threefold lower frequency of resting CD4 + T cells, compared with historical observations in U.S. patients.…”

“…We also analyzed the HIV-1 reservoir from patients infected with subtype A or D, with a limited number of subtype C infections, representative of the HIV-1 subtype distribution in Uganda [ 93 ]. It will be interesting to expand our findings to the most worldwide prevalent subtype C viruses [ 3 ]. It was also difficult to collect a comprehensive clinical history for each one of the 112 patients included in this study.…”

“…Although widespread global access to antiretroviral therapy (ART) has led to considerable reductions in HIV/AIDS morbidity and mortality [ 1 , 2 ], the HIV-1 epidemic continues to affect millions of people worldwide, with the highest burden in low- and middle-income countries (LMIC) [ 3 , 4 ], Unfortunately, while ART effectively controls HIV-1 replication in plasma to below current detection levels, HIV-1 persists mostly in latently-infected effector and transitional memory CD4 + T cells, with minimal decay despite prolonged ART [ 5 – 7 ]. This pool of latent proviruses is quickly established after infection, usually leading to a steady source of potentially replication-competent HIV-1 that persists indefinitely even in well suppressed cART-treated people living with HIV-1 (PLWH) [ 8 ].…”

“…To circumvent this problem, one avenue to eradicate the latent HIV-1 reservoir has been the “shock and kill” strategy, which involves activation of latent HIV-1 by latency reversal agents (LRA) in the presence of ART in conjunction with immunological approaches designed to purge the reactivated cells [ 11 – 13 ]. Numerous pre-clinical studies have used multitude of strategies, mainly based on LRAs, to re-activate the HIV-1 reservoir [ 3 , 8 , 13 , 14 ]; however, to date no LRA-based therapy—not even the promising histone deacetylase inhibitors (HDACIs)—have been able to successfully perturb the HIV-1 reservoir in human clinical trials [ 8 , 15 ]. It is clear that an incomplete understanding of the molecular nature of proviral latency has hampered progress in this area [ 16 ].…”