Evaluating Heterologous-Insert Prime-Boost HIV Vaccine Regimens in HIV-Uninfected Adults

One approach to developing a preventive HIV vaccine includes the use of a prime-boost vaccine strategy. This type of strategy involves two vaccines, given sequentially at different time points. The goal is to stimulate different parts of the immune system and enhance the body's overall immune response to HIV. In this study, participants will receive two HIV vaccines 3 months apart. Heterologous-insert prime-boost vaccine regimens, which use the same gene from different HIV-1 subtypes, may be more effective than traditional homologous insert prime-boost vaccine regimens at eliciting immune responses directed at epitopes that are highly prevalent, possibly leading to a more effective immune system response to the vaccine. The purpose of this study is to assess the safety and immunogenicity of a heterologous-insert prime-boost HIV vaccine regimen that uses inserts from different HIV-1 subtypes and different adenovirus vectors. This study will enroll healthy, HIV-uninfected people. Participants will be randomly assigned to one of five study groups: * Group 1 will receive the recombinant adenovirus serotype 35 (rAd35) Env A vaccine at baseline and the recombinant adenovirus serotype 5 (rAd5) Env A vaccine at Month 3. * Group 2 will receive the rAd35 Env A vaccine at baseline and the rAd5 Env B vaccine at Month 3. * Group 3 will receive the rAd35 Env A vaccine at baseline and at Month 3. * Group 4 will receive the rAd5 Env A vaccine at baseline and at Month 3. * Group 5 will receive the rAd5 Env A vaccine at baseline and the rAd5 Env B vaccine at Month 3. All vaccines will be injected into the upper arm. At both vaccination study visits, participants will undergo a physical exam, a medical and medication history review, a blood and urine collection, and questionnaires. Participants will receive counseling on HIV risk reduction and pregnancy prevention. After receiving the vaccine, participants will remain in the clinic for at least 30 minutes for observation and monitoring of side effects. For 3 days after each vaccination, participants will record their temperature and side effects in a symptom log. In addition to the vaccine study visits, other study visits will occur at Week 2, two weeks after the Month 3 visit, and at Months 4, 6, and 9, at which time various study procedures will be repeated. Participants will be contacted by study researchers once a year for 5 years for follow-up safety monitoring. Safety monitoring will not involve visiting a clinic except if a confirmatory HIV test is needed. Questions will assess health and adverse events. The primary objective of this study is to assess the safety and tolerability, as well as the ability, of a heterologous-insert prime-boost vaccine regimen using env inserts from different HIV-1 clades to increase T-cell responses. In addition, this study is evaluating the effectiveness of a heterologous-insert prime-boost and vector prime-boost vaccine regimen at increasing T-cell responses. The study will also compare the degree of polyfunctionality of insert specific T cells after vaccination within heterologous and homologous vector vaccine regimens.