T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.
Allison S ThomasKimberley L JonesRajesh T GandhiDeborah K McMahonJoshua C CyktorDora ChanSzu-Han HuangRonald TruongAlberto BosqueAmanda B MacedoColin KovacsErika BenkoJoseph J EronRonald J BoschChristina M LalamaSamuel J SimmensBruce D WalkerJohn W MellorsR Brad JonesPublished in: PLoS pathogens (2017)
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.
Keyphrases
- stem cells
- antiretroviral therapy
- hiv infected
- hiv positive
- human immunodeficiency virus
- cell therapy
- hiv aids
- hiv infected patients
- hiv testing
- hepatitis c virus
- induced apoptosis
- men who have sex with men
- cell cycle arrest
- poor prognosis
- dna methylation
- mesenchymal stem cells
- south africa
- cancer therapy
- signaling pathway
- transcription factor
- sars cov
- immune response
- gene expression
- single molecule
- dendritic cells
- newly diagnosed
- cell proliferation