Mucosal surfaces are the natural sites of transmission of many viruses — for HIV, transmission occurs at the genital and gastrointestinal surfaces. The gut mucosa is also a major reservoir for HIV, from which viruses can seed the bloodstream. Therefore, an HIV vaccine will probably need to generate effective mucosal immunity. In Nature Medicine, Belyakov and colleagues report that intra-rectal administration of a synthetic peptide vaccine induces specific cytotoxic T lymphocytes (CTLs) in the gut mucosa of macaques. Although the CTL response could not prevent infection after intra-rectal challenge, it had a positive impact on the course of infection.

This study is the first to directly compare mucosal and systemic immunization with the same vaccine in primates, and to assess the contribution of mucosal CTLs in clearing the mucosal viral reservoir. The peptide vaccine consisted of a mixture of four peptides, each containing a cluster of overlapping HIV-1 helper epitopes, and various CTL epitopes from simian immunodeficiency virus (SIV) Gag and Pol. Macaques were immunized either intra-rectally or subcutaneously in two cycles of four vaccine immunizations. In intra-rectally immunized animals, CTL responses were detected in both mucosal lymphoid sites and systemic lymphoid sites. By contrast, subcutaneous immunization predominantly elicited CTLs in the systemic compartment.

At 8 weeks after the immunizations, macaques were given an additional dose of vaccine, and 2 weeks later, were challenged intra-rectally with a pathogenic strain of simian/HIV, SHIV-Ku2. Animals immunized intra-rectally, in contrast to subcutaneously immunized animals, had plasma viral loads which rapidly fell below the level of detection.

So, does the mucosal CTL response correlate with control of infection at this site? At autopsy, 200 days after challenge with SHIV-Ku2, the CTL responses and viral loads in the gut mucosa were assessed. None of the intra-rectally immunized animals had detectable virus in the colon or jejenum, whereas subcutaneously immunized animals all had detectable virus.

This report provides the first evidence from primate studies in support of the idea that mucosal CTL responses are as significant as systemic responses in protection against mucosal transmission of HIV/SIV, and suggests that this will be an important consideration in the development of efficacious AIDS vaccines.