Background: A fundamental goal for an HIV vaccine is to induce long-lived protective immunity. However, in HIV vaccine trials conducted to date, humoral responses are modest and appear to wane rapidly after vaccination. Given the critical role of CD4 T cell help in the induction of affinity-matured, long-lived antibody responses, we extensively characterized CD4 responses developed using a wide range of previously studied vaccine candidates and adjuvants. Methodology: Cryopreserved peripheral blood mononuclear cells were obtained from samples corresponding to peak immunogenicity times of several HIV vaccines including ALVAC alone delivered via different routes, ALVAC prime/ AIDSVAX boosts, ALVAC prime/ Env protein boosts, DNA prime/ Ad5 boost, subtype B gp120 alone, and MVA alone. Chronically infected HIV specimens were used as reference. HIV-specific CD4 T cell responses were assessed by intracellular cytokine staining using multicolor flow cytometry. Results: HIV-specific CD4 T cell responses were detectable in all vaccines and patients, however, the magnitude, cytokine profile and protein dominance varied substantially. Overall, PBMC from vaccine recipients primarily targeted Env, compared to chronic HIV specimens that primarily targeted Gag. ALVAC immunizations delivered intradermally or loaded on autologous dendritic cells generated CD4 T cell responses to Env-derived peptides while intramuscular delivery elicited responses targeting Gag peptides. Env protein boosting of intramuscular ALVAC primes overwhelmingly shifted the response to Env. In this regard, boosting with oligomeric gp160 had a stronger effect than bivalent gp120. CD4 T cells responding to ALVAC vaccination alone predominantly produced TNFα and IL-21 in response to Env, whereas Gag invoked more IFNγ than IL-21. Oligomeric gp160-boosted PBMCs produced TNFα and IFNγ in response to both Env and Gag, while the response in bivalent gp120-boosted PBMC consisted of TNFα, IFNγ, and IL-21, albeit as mostly single-cytokine producing cells. MVA immunizations, either intradermal or intramuscular, overwhelmingly generated more to Env peptides than Gag specific responses. Using principal component analysis (PCA), the induced response patterns showed a very distinct cytokine profile that only partially overlapped with the CD4 T cell responses seen in natural HIV infection. Conclusions: Immunization vectors and antigens differentially influence the CD4+ T cell response. Vaccine-specific immune responses vary drastically from those developed through natural HIV-1 infection. Ongoing analyses of specific CD4 T cell responses induced by various vaccination vectors and delivery routes may elucidate optimal means of invoking strong antibody responses in HIV vaccine recipients.
CROI Conference
