Abstract
The design of an effective HIV-1 vaccine remains a major challenge. Several vaccine strategies based on viral vectors have been evaluated in preclinical and clinical trials, with largely disappointing results. Integrase defective lentiviral vectors (IDLV) represent a promising vaccine candidate given their ability to induce durable and protective immune responses in mice after a single immunization. Here, we evaluated the immunogenicity of a SIV-based IDLV in nonhuman primates. Six rhesus monkeys were primed intramuscularly with IDLV-Env and boosted with the same vector after 1 year. A single immunization with IDLV-Env induced broad humoral and cellular immune responses that waned over time but were still detectable at 1 year postprime. The boost with IDLV-Env performed at 1 year from the prime induced a remarkable increase in both antibodies and T-cell responses. Antibody binding specificity showed a predominant cross-clade gp120-directed response. Monkeys' sera efficiently blocked anti-V2 and anti-CD4 binding site antibodies, neutralized the tier 1 MW965.26 pseudovirus and mediated antibody-dependent cellular cytotoxicity (ADCC). Durable polyfunctional Env-specific T-cell responses were also elicited. Our study demonstrates that an IDLV-Env-based vaccine induces functional, comprehensive, and durable immune responses in Rhesus macaques. These results support further evaluation of IDLV as a new HIV-1 vaccine delivery platform.
Highlights
Despite major improvements in the morbidity and mortality associated with HIV-1 infection from introduction of antiretroviral therapy, the development of an effective HIV-1 vaccine for prevention remains a global priority
We recently described a novel delivery system based on selfinactivating (SIN) integrase defective lentiviral vector (IDLV) capable of inducing comprehensive and persistent immune responses after a single immunization in mice.[9,10,11]
We show for the first time that a single immunization with Integrase defective lentiviral vectors (IDLV)-Env in rhesus macaques induced prolonged antibody and T-cell responses, still detectable after 1 year
Summary
Despite major improvements in the morbidity and mortality associated with HIV-1 infection from introduction of antiretroviral therapy, the development of an effective HIV-1 vaccine for prevention remains a global priority. Recent studies have provided insight into critical elements of an effective vaccine.[1] The correlates of protection of the only AIDS vaccine trial in humans showing some efficacy, the ALVAC-prime AIDSVAX-boost RV144 trial,[2] included a direct correlation with IgG anti-V1/V2 non-neutralizing antibodies (Abs), antibody-dependent cellular cytotoxicity (ADCC) and an inverse correlation with anti-Env IgA response in plasma.[3,4,5] the protection was short lived with V1/V2 antibody (Ab) levels waning over 6 months after a boost.[4,6] Different strategies have been investigated for enhancing the durability of Ab responses against HIV, including repeated boosts, use of novel adjuvants, and a combination of heterologous prime-boost regimens.[7] Interestingly, a recent study comparing DNA or protein vaccination alone to DNA plus protein boost at the same site in nonhuman primates (NHP) demonstrated that strategies to enhance magnitude of Ab responses differ from those designed to enhance durability. Simultaneous administration of DNA and protein improved magnitude, durability, and increased mucosal dissemination of the induced Abs in immunized rhesus macaques compared to the use of DNA or protein used alone during the immunization.[8]
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