T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.

TitleT-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.
Publication TypeJournal Article
Year of Publication2017
AuthorsThomas AS, Jones KL, Gandhi RT, McMahon DK, Cyktor JC, Chan D, Huang S-H, Truong R, Bosque A, Macedo AB, Kovacs C, Benko E, Eron JJ, Bosch RJ, Lalama CM, Simmens S, Walker BD, Mellors JW, R Jones B
JournalPLoS Pathog
Volume13
Issue9
Paginatione1006629
Date Published2017 Sep
ISSN1553-7374
KeywordsAnti-Retroviral Agents, CD8-Positive T-Lymphocytes, Enzyme-Linked Immunospot Assay, HIV Infections, Humans, nef Gene Products, Human Immunodeficiency Virus, Polymerase Chain Reaction, Virus Latency
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.

DOI10.1371/journal.ppat.1006629
Alternate JournalPLoS Pathog.
PubMed ID28931091
PubMed Central IDPMC5624641
Grant ListP30 AI117970 / AI / NIAID NIH HHS / United States