The HIV-2 reservoir: lessons from HIV-1 and knowledge gaps

HIV-2 establishes a persistent viral reservoir despite its lower replication capacity and attenuated clinical course compared with HIV-1. Some studies suggest that the HIV-2 cellular reservoir is substantially smaller, with total HIV-2 DNA levels in peripheral blood mononuclear cells typically 1-2log₁₀ lower than those observed in HIV-1, even in individuals on long-term suppressive antiretroviral therapy. Importantly, HIV-2 proviral DNA remains detectable for many years, indicating durable persistence despite low-level replication. Detailed analyses of reservoir composition suggest that HIV-2 proviruses are preferentially localized within transitional memory CD4⁺ T-cells, whereas central memory T-cells appear relatively spared. This skewed distribution was suggested to be linked with higher expression of restriction factors and differential expression of coreceptors, highlighting the role of host determinants in shaping the reservoir. Genomic analyses reveal that the majority of HIV-1 proviruses are defective and that clonal expansion of infected cells can occur, but whether this is also applicable to HIV-2 remains unknown. Besides, the inducibility and replication competence of these intact HIV-2 proviruses remain largely undefined due to the lack of validated functional assays on HIV-2. Data on tissue reservoirs are limited, but available evidence suggests that lymphoid tissues and mucosal sites may serve as potential HIV-2 reservoirs. The contribution of myeloid cells to HIV-2 persistence remains unclear, despite efficient infection of macrophages ex vivo. Overall, current data support the existence of a smaller, more restricted, and potentially less inducible HIV-2 reservoir, but major knowledge gaps remain in terms of dynamics, tissue distribution, and cure studies.