T-Cell Responses Targeting HIV Nef Uniquely Correlate with Infected Cell Frequencies After Long-term Antiretroviral Therapy.

Authors

Allison S Thomas, George Washington UniversityFollow
Kimberley L Jones, George Washington University
Rajesh T Gandhi
Deborah K McMahon
Joshua C Cyktor
Dora Chan, George Washington University
Szu-Han Huang, George Washington UniversityFollow
Ronald Truong, George Washington University
Alberto Bosque, George Washington University
Amanda B Macedo, George Washington UniversityFollow
Colin Kovacs
Erika Benko
Joseph J Eron
Ronald J Bosch
Christina M Lalama
Samuel SimmensFollow
Bruce D Walker
John W Mellors
R Brad Jones, George Washington UniversityFollow

Document Type

Journal Article

Publication Date

9-20-2017

Journal

PLoS Pathogens

Volume

13

Issue

9

DOI

10.1371/journal.ppat.1006629

Abstract

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.

Comments

Reproduced with permission of PLoS Pathogens.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

APA Citation

Thomas, A., Jones, K., Gandhi, R., McMahon, D., Cyktor, J., Chan, D., Huang, S., Truong, R., Bosque, A., Macedo, A., Kovacs, C., Benko, E., Eron, J., Bosch, R., Lalama, C., Simmens, S., Walker, B., Mellors, J., & Jones, R. (2017). T-Cell Responses Targeting HIV Nef Uniquely Correlate with Infected Cell Frequencies After Long-term Antiretroviral Therapy.. PLoS Pathogens, 13 (9). http://dx.doi.org/10.1371/journal.ppat.1006629

Peer Reviewed

1

Open Access

1