HSV-2 Rectal Infection Increases Susceptibility to Rectal SIV Infection Even in the Context of SIVΔnef Infection

CD4⁺ T cells that express high levels of α₄β₇ are particularly susceptible to HIV/SIV infection and their frequency at the rectal site of SIV exposure correlates with SIV acquisition. Blocking α₄β₇ reduces susceptibility to vaginal SIV infection. We have shown that vaginal and rectal HSV-2 infection in macaques increases the frequency of α₄β₇^high CD4⁺ T cells and that, in vaginal tissue, this correlates with increased susceptibility to SHIV_SF162P3. Using our unique model of rectal HSV-2 infection in macaques in combination with the SIVΔnef model of attenuated SIV infection, we found that HSV-2 rectal infection increases the susceptibility of macaques to rectal SIV wild-type (SIVwt) even in SIVΔnef-infected animals. SIVwt/HSV-2 co-infected animals had increased concentrations of IL-17, EGF, and CXCL8 in their rectal fluids, although, intriguingly, they had lower SIV viral loads in mesenteric lymph nodes than animals only infected with SIVwt. Thus, HSV-2 increases susceptibility to rectal SIV infection undermining the protective effects of SIVΔnef. Analysis of additional data will reveal if HSV-2-driven increase in α₄β₇ and/or other HSV-2 induced changes in the rectal mucosa correlate with the HSV-2-associated increase in SIV infection. This work will help to identify key determinants of HIV susceptibility suggesting novel paths to HIV prevention.