Lymph node remodelling underlies the attenuated form of HIV/AIDS in people with HIV-2

HIV-2 infection is associated with low-to-undetectable plasma viral load, broad and sustained specific antibody and T cell responses, and a slow course of CD4 T cell decline, even in the absence of antiretroviral therapy (ART). Here, we investigated the secondary lymphoid organs of people with HIV-2 (PWH2) as compared to people with HIV-1 (PWH1) and seronegative subjects. We found active HIV-2 replication and major disruption of lymph node architecture in PWH2, also attested by the alterations that we demonstrated in the blood counterparts of follicular T and B cells. These findings were corroborated by in vitro infection assays using tonsil organ cultures and HIV-2 or HIV-1 primary isolates with distinct co-receptor usage, CCR5 or CXCR4, which showed significant HIV-2 cytopathogenicity associated with post-transcriptional control of HIV-2 replication, revealed by high titres of cell-associated viral DNA and mRNA transcripts but reduced HIV-2 protein production. Overall, our findings support a major impact of HIV-2 on secondary lymphoid tissue organisation throughout the disease course, stressing the relevance of this neglected infection to understand host-pathogen equilibrium in retroviral zoonoses and to identify strategies towards a functional HIV cure.