The field of HIV-1 vaccinology has primarily focused on identifying the immunodominant responses to determine suitable immunogens that might be included in an HIV-1 vaccine. However, focusing on this approach in isolation has disadvantages. The main problem is that the enormous sequence variability of HIV-1 dictates that other epitopes be identified. This issue is especially poignant in light of the recent failure of the Merck vaccine trial or Step Study, as the limited breadth of CD8 T lymphocyte (CD8-TL) response induced by this vaccine likely contributed to its lack of efficacy. In an attempt to identify novel targets to increase the breadth of a CD8-TL based vaccine, the current proposal aims to study a unique class of epitopes. Cryptic epitopes (CE) are translated from alternate reading frames (ARF) and not the main reading frame used to synthesize the functional proteins. We show data that CE are commonly targeted in primary and chronic HIV-1 infection. This finding is justification for aim 1 of the current proposal which will characterize CE comprehensively using overlapping peptides spanning the ARF of the HIV-1 proteome. This will yield valuable information about cryptic epitopes that are frequently targeted and whether they correlate with viral control in the setting of chronic HIV infection (CHI).
Aim 2 of the current proposal will determine the biological significance of these CE responses in the setting of primary HIV infection (PHI). This attribute will be measured by the propensity of the CE to escape immune pressure and to revert to wild type when the mutated virus is transmitted to a non-HLA-I matched recipient. If our hypothesis were proven to be correct, the vaccine field can begin to design vectors that induce CE responses, thereby significantly increasing the number of CD8-TL targets without necessarily increasing the size of the insert. Lastly, in aim 3 we hypothesize that relatively inefficient protein production may thereby allow for increased CE responses. Analysis of the PBMC samples from recipients of two different HIV-1 vaccines, being tested in clinical trials, allows us the unique opportunity to test this hypothesis as is detailed in the application. Taken together, this proposal will not only determine the biologic significance of CE responses but also determine if these responses are induced using the current recombinant HIV-1 vaccines. Such information will be extremely helpful for future HIV-1 vaccine design. This proposal aims to understand the full breadth and functional features of cytotoxic T lymphocytes that may be induced during both HIV-1 infection and HIV-1 vaccination. This information will be highly relevant and directly applicable to the design of an HIV-1 vaccine.

Public Health Relevance

This proposal aims to understand the full breadth and functional features of cytotoxic T lymphocytes that may be induced during both HIV-1 infection and HIV-1 vaccination. This information will be highly relevant and directly applicable to the design of an HIV-1 vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084772-05
Application #
8526357
Study Section
Special Emphasis Panel (ZAI1-SV-A (M2))
Program Officer
Pensiero, Michael N
Project Start
2009-09-11
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$451,070
Indirect Cost
$125,624
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Williams, LaTonya D; Amatya, Nilesh; Bansal, Anju et al. (2014) Immune activation is associated with CD8 T cell interleukin-21 production in HIV-1-infected individuals. J Virol 88:10259-63
Yan, Jiyu; Sabbaj, Steffanie; Bansal, Anju et al. (2013) HIV-specific CD8+ T cells from elite controllers are primed for survival. J Virol 87:5170-81
Williams, LaTonya D; Bansal, Anju; Sabbaj, Steffanie et al. (2011) Interleukin-21-producing HIV-1-specific CD8 T cells are preferentially seen in elite controllers. J Virol 85:2316-24
Heath, Sonya L; Sabbaj, Steffanie; Bansal, Anju et al. (2011) CD8 T-cell proliferative capacity is compromised in primary HIV-1 infection. J Acquir Immune Defic Syndr 56:213-21
Akinsiku, Olusimidele T; Bansal, Anju; Sabbaj, Steffanie et al. (2011) Interleukin-2 production by polyfunctional HIV-1-specific CD8 T cells is associated with enhanced viral suppression. J Acquir Immune Defic Syndr 58:132-40
Bansal, Anju; Carlson, Jonathan; Yan, Jiyu et al. (2010) CD8 T cell response and evolutionary pressure to HIV-1 cryptic epitopes derived from antisense transcription. J Exp Med 207:51-9