Immunization by exposure to live virus (SIV(mne)/HIV-2(287)) during antiretroviral drug prophylaxis may reduce risk of subsequent viral challenge

RATIONALE/STUDY DESIGN: A major challenge in the development of HIV vaccines is finding immunogens that elicit protection against a broad range of viral strains. Immunity to a narrow range of viral strains may protect infants of HIV-infected women or partners discordant for HIV. We hypothesized that immunization to the relevant viral variants could be achieved by exposure to infectious virus during prophylaxis with antiretroviral drugs. To explore this approach in an animal model, macaques were exposed to live virus (SIV(mne) or HIV-2(287)) during prophylaxis with parenteral tenofovir and humoral and cellular immune responses were quantified. Subsequently, experimental animals were challenged with homologous virus to evaluate protection from infection, and if infection occurred, the course of disease was compared to control animals. Experimental animals uninfected with SIV(mne) were challenged with heterologous HIV-2(287) to assess resistance to retroviral infection. METHODOLOGY/PRINCIPAL FINDINGS: Juvenile female Macaca nemestrina (N = 8) were given ten weekly intravaginal exposures with either moderately (SIV(mne)) or highly (HIV-2(287)) pathogenic virus during tenofovir prophylaxis. Tenofovir protected all 8 experimental animals from infection, while all untreated control animals became infected. Specific non-neutralizing antibodies were elicited in blood and vaginal secretions of experimental animals, but no ELISPOT responses were detected. Six weeks following the cessation of tenofovir, intravaginal challenge with homologous virus infected 2/4 (50%) of the SIV(mne)-immunized animals and 4/4 (100%) of the HIV-2(287)-immunized animals. The two SIV(mne)-infected and 3 (75%) HIV-2(287)-infected had attenuated disease, suggesting partial protection. CONCLUSIONS/SIGNIFICANCE: Repeated exposure to SIV(mne) or HIV-2(287), during antiretroviral prophylaxis that blocked infection, induced binding antibodies in the blood and mucosa, but not neutralizing antibodies or specific cellular immune responses. Studies to determine whether antibodies are similarly induced in breastfeeding infants and sexual partners discordant for HIV infection and receiving pre-exposure antiretroviral prophylaxis are warranted, including whether these antibodies appear to confer partial or complete protection from infection.