Broad and persistent Gag-specific CD8+ T-cell responses are associated with viral control but rarely drive viral escape during primary HIV-1 infection

ABSTRACT While prior studies have demonstrated that CD8 T cell responses to cryptic epitopes (CE) are readily detectable during HIV-1 infection, their ability to drive escape mutations following acute infection is unknown. We predicted 66 CE in a Zambian acute infection cohort based on escape mutations occurring within or near the putatively predicted HLA-I-restricted epitopes. The CE were evaluated for CD8 T cell responses for patients with chronic and acute HIV infections. Of the 66 predicted CE, 10 were recognized in 8/32 and 4/11 patients with chronic and acute infections, respectively. The immunogenic CE were all derived from a single antisense reading frame within pol. However, when these CE were tested using longitudinal study samples, CE-specific T cell responses were detected but did not consistently select for viral escape mutations. Thus, while we demonstrated that CE are immunogenic in acute infection, the immune responses to CE are not major drivers of viral escape in the initial stages of HIV infection. The latter finding may be due to either the subdominant nature of CE-specific responses, the low antigen sensitivity, or the magnitude of CE responses during acute infections. IMPORTANCE Although prior studies demonstrated that cryptic epitopes of HIV-1 induce CD8 T cell responses, evidence that targeting these epitopes drives HIV escape mutations has been substantially limited, and no studies have addressed this question following acute infection. In this comprehensive study, we utilized longitudinal viral sequencing data obtained from three separate acute infection cohorts to predict potential cryptic epitopes based on HLA-I-associated viral escape. Our data show that cryptic epitopes are immunogenic during acute infection and that many of the responses they elicit are toward translation products of HIV-1 antisense reading frames. However, despite cryptic epitope targeting, our study did not find any evidence of early CD8-mediated immune escape. Nevertheless, improving cryptic epitope-specific CD8 T cell responses may still be beneficial in both preventative and therapeutic HIV-1 vaccines.

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HIV-1-Specific Interleukin-21+ CD4+ T Cell Responses Contribute to Durable Viral Control through the Modulation of HIV-Specific CD8+ T Cell Function

Journal of Virology ◽

10.1128/jvi.02030-10 ◽

2010 ◽

Vol 85 (2) ◽

pp. 733-741 ◽

Cited By ~ 135

Author(s):

M. F. Chevalier ◽

B. Julg ◽

A. Pyo ◽

M. Flanders ◽

S. Ranasinghe ◽

...

Keyword(s):

T Cell ◽

Cell Function ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Viral Control ◽

Cell Responses ◽

T Cell Function ◽

Interleukin 21 ◽

Hiv 1

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Immune-driven recombination and loss of control after HIV superinfection

Journal of Experimental Medicine ◽

10.1084/jem.20080281 ◽

2008 ◽

Vol 205 (8) ◽

pp. 1789-1796 ◽

Cited By ~ 75

Author(s):

Hendrik Streeck ◽

Bin Li ◽

Art F.Y. Poon ◽

Arne Schneidewind ◽

Adrianne D. Gladden ◽

...

Keyword(s):

T Cell ◽

De Novo ◽

Subsequent Development ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Immune Selection ◽

Viral Control ◽

Acute Hiv Infection ◽

Cell Responses

After acute HIV infection, CD8+ T cells are able to control viral replication to a set point. This control is often lost after superinfection, although the mechanism behind this remains unclear. In this study, we illustrate in an HLA-B27+ subject that loss of viral control after HIV superinfection coincides with rapid recombination events within two narrow regions of Gag and Env. Screening for CD8+ T cell responses revealed that each of these recombination sites (∼50 aa) encompassed distinct regions containing two immunodominant CD8 epitopes (B27-KK10 in Gag and Cw1-CL9 in Env). Viral escape and the subsequent development of variant-specific de novo CD8+ T cell responses against both epitopes were illustrative of the significant immune selection pressures exerted by both responses. Comprehensive analysis of the kinetics of CD8 responses and viral evolution indicated that the recombination events quickly facilitated viral escape from both dominant WT- and variant-specific responses. These data suggest that the ability of a superinfecting strain of HIV to overcome preexisting immune control may be related to its ability to rapidly recombine in critical regions under immune selection pressure. These data also support a role for cellular immune pressures in driving the selection of new recombinant forms of HIV.

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Faculty Opinions recommendation of Loss of viral control in early HIV-1 infection is temporally associated with sequential escape from CD8+ T cell responses and decrease in HIV-1-specific CD4+ and CD8+ T cell frequencies.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1020332.232525 ◽

2004 ◽

Author(s):

Luis J Montaner

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Control ◽

Cell Responses ◽

Hiv 1

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Polyfunctional CD8+ T-Cell Response to Autologous Peptides from Protease and Reverse Transcriptase of HIV-1 Clade B

Current HIV Research ◽

10.2174/1570162x17666191017105910 ◽

2019 ◽

Vol 17 (5) ◽

pp. 350-359

Author(s):

Liliana Acevedo-Saenz ◽

Federico Perdomo-Celis ◽

Carlos J. Montoya ◽

Paula A. Velilla

Keyword(s):

T Cell ◽

Reverse Transcriptase ◽

Cellular Response ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Effective Vaccine ◽

Cell Responses ◽

Clade B ◽

Hiv 1

Background: : The diversity of the HIV proteome influences the cellular response and development of an effective vaccine, particularly due to the generation of viral variants with mutations located within CD8+ T-cell epitopes. These mutations can affect the recognition of the epitopes, that may result in the selection of HIV variants with mutated epitopes (autologous epitopes) and different CD8+ T-cell functional profiles. Objective:: To determine the phenotype and functionality of CD8+ T-cell from HIV-infected Colombian patients in response to autologous and consensus peptides derived from HIV-1 clade B protease and reverse transcriptase (RT). Methods:: By flow cytometry, we compared the ex vivo CD8+ T-cell responses from HIV-infected patients to autologous and consensus peptides derived from HIV-1 clade B protease and RT, restricted by HLA-B*35, HLA-B*44 and HLA-B*51 alleles. Results:: Although autologous peptides restricted by HLA-B*35 and HLA-B*44 did not show any differences compared with consensus peptides, we observed the induction of a higher polyfunctional profile of CD8+ T-cells by autologous peptides restricted by HLA-B*51, particularly by the production of interferon-γ and macrophage inflammatory protein-1β. The response by different memory CD8+ T-cell populations was comparable between autologous vs. consensus peptides. In addition, the magnitude of the polyfunctional response induced by the HLA-B*51-restricted QRPLVTIRI autologous epitope correlated with low viremia. Conclusion:: Autologous peptides should be considered for the evaluation of HIV-specific CD8+ Tcell responses and to reveal some relevant epitopes that could be useful for therapeutic strategies aiming to promote polyfunctional CD8+ T-cell responses in a specific population of HIV-infected patients.

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