Dr. David Watkins Research Laboratory

Dr. Watkins Research Laboratory

Description of Research

With nearly 7,000 people dying each day of HIV/AIDS, the development of an effective vaccine remains one of the world’s top public health priorities. A better understanding of rare cases where HIV replication is brought under control by the immune system may facilitate the development of a vaccine for HIV. Elite controllers (ECs) of HIV infection are a small number of individuals that spontaneously control viral replication in the absence of antiretroviral treatment and thus do not progress to AIDS. The majority of these ECs are positive for HLA-B*27 and HLA-B*57, implying that CD8+ T-cells play an important role in elite control of HIV.

Simian immunodeficiency virus (SIV) infection of Indian rhesus macaques is an invaluable model to study effective immune responses against the AIDS virus. Similar to elite control of HIV in humans, a limited number of SIV-infected Indian rhesus macaques also show some level of control of replication of the pathogenic SIVmac239 virus. This positive outcome is associated with the expression of the macaque MHC class I alleles Mamu-B*08 and Mamu-B*17. Remarkably, 50% of Mamu-B*08+ macaques show some level of control of SIVmac239 replication. We have recently discovered that Mamu-B*08 and HLA-B*27 bind many of the same peptides. Despite being divergent at 28 amino acid positions, these molecules share similar peptide binding motifs, including an identical position 2-arginine primary anchor. Both MHC class I molecules also exhibit considerable overlap in preferred binding residues at the other dominant position 1 and position 9 residues.

The acute phase CD8+ T cell response in both HIV-infected HLA-B*-57 or HLA-B*-27 positive humans and SIVmac239-infected Mamu-B*08 positive macaques is governed by T cells that identify epitopes bound by the elite control associated allele. Three Mamu-B*08 restricted CD8 T cells responses make up for more than half of the T cell responses against the virus in Mamu-B*08 positive EC; these CD8 T cells recognize Vif172-179RL8, Vif123-131RL9, and Nef137-146RL10.

We have recently used a recombinant yellow fever virus 17D (rYF17D) prime, followed by a recombinant Adenovirus type-5 (rAd5) boost regimen to vaccinate Mamu-B*08+ animals with two regions of the SIVmac239 proteome; Vif 3’ (amino acids 102-214; includes the Vif123-131RL9 and Vif172-179RL8 epitopes) and Nef (amino acids 45-210; includes the Nef137-146RL10 epitope). These vaccinated animals developed CD8+ T-cell responses directed against these three immunodominant epitopes and controlled viral replication after repeated high-dose challenges with SIVmac239. High frequencies of CD8+ T cells against these Vif and Nef epitopes in the blood, lymph nodes and colon, were associated with viral control. Moreover, the frequency of the Nef137-146RL10-specific response correlated significantly with reduced acute phase viremia. Viral loads in these macaques were significantly lower than those measured in control Mamu-B*08+ animals that were vaccinated with two regions of SIVmac239 that do not encode any known Mamu-B*08-restricted epitope. Our findings indicate that narrowly targeted vaccine-induced virus-specific CD8+ T cell responses can control replication of the AIDS virus. Understanding why these Mamu-B*08-restricted CD8+ T-cell responses control viral replication when most other T-cell responses do not may enable the design of an effective approach to HIV vaccination.

Our research team will also investigate novel ways to make an effective vaccine against HIV using the yellow fever vaccine. The live-attenuated yellow fever vaccine virus YF17D is one of the most successful human vaccines ever developed. In humans, YF17D triggers several innate immune pathways, which likely contributes to its high immunogenicity. Vaccination results in polyvalent adaptive immune responses consisting of effector CD8+ T-cells and a mixed TH1/TH2 CD4+ T-cell profile. We are interested in exploring the idea that we can insert fragments of the AIDS virus into the yellow fever vaccine and use it to induce immune responses against the AIDS virus.