Massive and persistent CD4+ T cell depletion is a hallmark of HIV infection, being associated with impairment of cellular immunity and opportunistic infections. The contribution of CD4+ T cell depletion to SIV/HIV-associated gut dysfunction is unknown. African Green Monkeys (AGMs), a species that do not progress to AIDS, partially recover mucosal CD4+ T cells during chronic infection and maintain gut integrity. We assessed the impact of prolonged experimental CD4+ T cell depletion on the gut integrity and natural history of SIV infection in AGMs.
Six AGMs were infected intravenously with 300TCID50 SIVsab. All animals received an anti α-CD4 antibody intravenously every three weeks, starting from 21 days post infection (dpi). Plasma viral loads (PVLs), absolute counts, proliferation and activation status of T cells, systemic and local immune activation and inflammation, gut integrity, and cardiovascular disease onset were monitored throughout the follow-up.
Complete ablation of CD4+ T cells in blood and greater than 90% depletion in intestine and lymph nodes was achieved. PVLs peaked at 107 viral RNA copies/mL at 10 dpi, followed by a 4-log decrease by 28 dpi. PVLs were lower compared to SIV-infected historical AGM controls and were even undetectable in some CD4-depleted AGMs. No significant changes in T cell immune activation and proliferation levels occurred in the CD4-depleted AGMs. A transient increase of the inflammatory cytokines and chemokines (IL-1RA, Rantes, Eotoxin, MCP-1, I-TAC, MIF and IP-10) occurred only during acute infection but was resolved prior to chronic infection. Absence of gut damage was observed in situ and through the testing of iFABP, Zonulin, and sCD14 which remained stable during the follow up. sCD163 transiently increased during acute infection.
Despite a major and persistent (over 1 year) depletion of CD4+ T cells in blood and tissues, AGMs remained healthy and did not progress to AIDS. Gut integrity was maintained in spite of profound CD4+ T cell loss. As such, our results suggest that CD4+ T cell depletion, in the absence of increased inflammation and immune activation is not a determinant factor for SIV-related gut dysfunction. Our results also indicate that AGMs’ AIDS-resistance is independent of the CD4+ T cells.