Abstract
Rationale/Study designA 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 (SIVmne or HIV-2287) 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 SIVmne were challenged with heterologous HIV-2287 to assess resistance to retroviral infection.Methodology/Principal findingsJuvenile female Macaca nemestrina (N = 8) were given ten weekly intravaginal exposures with either moderately (SIVmne) or highly (HIV-2287) 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 SIVmne-immunized animals and 4/4 (100%) of the HIV-2287-immunized animals. The two SIVmne-infected and 3 (75%) HIV-2287-infected had attenuated disease, suggesting partial protection.Conclusions/SignificanceRepeated exposure to SIVmne or HIV-2287, 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.
Highlights
HIV causes a persistent infection that, without treatment, results in high mortality
Multiple peripheral blood mononuclear cells (PBMC) specimens were negative for virus by coculture and polymerase chain reaction assay (PCR) (6–10μg DNA/animal collected over study weeks 15 to 20) as was inguinal lymphoid tissue collected at study week 19
Our strategy to immunize macaques to a specific strain of virus by exposure to live SIVmne or HIV-2287 during protective antiretroviral prophylaxis with tenofovir resulted in the generation of specific antibodies by all animals
Summary
HIV causes a persistent infection that, without treatment, results in high mortality. Considerable effort has been devoted to the development of a vaccine that can prevent infection (reviewed [1]). Initial efforts to generate a protective HIV vaccine were largely focused on eliciting protective immunity via broadly neutralizing antibodies (reviewed [2]). This approach was pursued due to observations that sera of chronically HIV-infected individuals neutralized significant numbers of heterologous virus isolates [3], and the transfer of sera containing neutralizing HIV/SIV antibodies and neutralizing monoclonal antibodies have protected experimental animals from mucosal challenge [4,5,6]. The breadth of vaccine-elicited neutralizing antibodies has generally been narrow (reviewed [7]). Problematic is that in most individuals, the induction of broadly neutralizing antibodies requires a series of mutations in V-beta chains that occurs over months to years [8]
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