The ability of HIV to replicate in secondary lymphoid organs (SLO) and disrupt lymph node (LN) architecture are considered main determinants of disease progression. HIV-2+ individuals feature slow rate of CD4 T cell decline and AIDS progression, maintain low to undetectable viremia in the presence of disseminated viral reservoirs, and high titers of broadly neutralizing antibodies throughout the disease course. Thus, this naturally-occurring attenuated infection provides a unique setting to investigate HIV-host interplay in SLO that has been poorly explored.
We conducted a parallel study of 1) archived LN from HIV-2+, HIV-1+ and seronegative individuals using immunochemistry, and 2) in vitro infection of tonsil organ cultures (TOCs) with HIV-2 and HIV-1 primary isolates with different co-receptor usage.
HIV-2+ individuals featured very different CD4 T cell counts at the time of lymph node collection (744, 444, 255 and 73 cells/µl), but in all of them we could find viral replication, as assessed by p27 staining. Using the in vitro model we further confirmed comparable levels of HIV-2 and HIV-1 replication in terms of proviral DNA and gag mRNA levels, although the amount of cells producing virus (KC57+) were significantly lower in HIV-2 X4 than in HIV-1 X4 isolates. Moreover, the pattern of viral impact on the cellular populations was remarkably reproducible between TOCs, with a preferential depletion of follicular CD4 T cells (TFH), particularly upon infection with HIV-2 X4. Interestingly follicular regulatory CD4 T cells (TFR) were less depleted and CXCR5+CD8+ T cells were maintained. Importantly, LN from HIV-2+ patients featured a progressive CD4 T cell depletion in agreement with blood CD4 T cell decline, which was more marked than in the 12 HIV-1+ LN evaluated. Of note, FOXP3+ and CD8 T cells were preserved in non-germinal center areas. Regarding LN architecture, we found significant collagen deposition with reticulin network disruption, even in early stage HIV-2+ individuals, as compared to both seronegatives (n=8) and HIV-1+. Additionally, HIV-2+ LN featured less hyperplasic germinal centres than HIV-1+ LN, but their morphology were more disrupted.
Altogether, our data support continuous viral replication in SLO and an altered germinal center organization in HIV-2 infection. Their contribution to the benign HIV-2 course deserves further investigation that may reveal new strategies to control HIV reservoirs.