Augmented HIV-Specific Interferon-Gamma Responses, But Impaired Lymphoproliferation During Interruption of Antiretroviral Treatment Initiated in Primary HIV Infection

Abstract

Background Antiretroviral therapy (ART) introduced during primary HIV infection followed by treatment interruption (TI) is postulated to enhance virologic control through induction of HIV-specific CD4+ T-cells, which foster virus-specific CD8+ T-cells that suppress virus replication. This hypothesis was evaluated in 21 subjects enrolled in ACTG 709, a substudy of ACTG 371, which prospectively evaluated subjects who received ≥1 year of ART initiated in acute or recent HIV infection followed by TI. Methods Lymphoproliferation was assessed by [methyl-3H]thymidine incorporation and HIV-specific CD8+ T-cell interferon-gamma responses by enzyme-linked immunospot-forming (ELISPOT) assays. Virologic success was defined as sustained viral load <5,000 copies/mL for 24 weeks after TI. Results HIV-specific lymphoproliferative responses were detected at least once in 5 (24%) of 21 subjects, were generally transient, and were unrelated to HIV-specific interferon-gamma responses (p>0.4). HIV-specific CD8+ interferon-gamma responses increased after 48 weeks of ART (p=0.03), but failed to predict virologic success (p=0.18). Compared to seronegative subjects, lymphoproliferation to Candida, cytomegalovirus, and alloantigens was similar in HIV-infected subjects during ART, but lower during TI (p≤0.04). Conclusion HIV-specific CD8+ T-cell interferon-gamma responses expand during ART following primary HIV infection, but are not related to HIV-specific lymphoproliferative responses nor virologic success. Impaired non-HIV antigen-specific lymphoproliferation associated with TI suggests this strategy could be deleterious.

Prevalence and Associations of Psychological Distress, HIV Infection and HIV Care Service Utilization in East Zimbabwe

“…Our results provide robust scientific evidence from a large, general population survey to support findings of an association between poor mental health and reduced adherence to ART medication from earlier, largely small-scale, clinic-based studies in sub-Saharan Africa [ 20 – 25 ]. An important limitation of the study, however, is its reliance on cross-sectional data.…”

“…In cross-sectional studies conducted amongst attendees at HIV care facilities in sub-Saharan Africa, psychological distress has been associated with treatment interruptions and sub-optimal adherence to ART, increasing the potential for virological failure, poor disease outcomes and further spread of infection [ 20 – 25 ]. However, the preponderance of evidence from these populations may create bias towards health seeking individuals whose symptoms are more severe such that they warrant institution-based care.…”

Characterization of Peripheral and Mucosal Immune Responses In Rhesus Macaques on Long-Term Tenofovir and Emtricitabine Combination Antiretroviral Therapy

“…Candida- specific T cells were not affected by ART or chronic infection, which is not surprising since the animals (except AA47) remained healthy overall. Connick et al detected an increase in Candida -specific lymphoproliferative responses in HIV-infected individuals after 48 weeks on ART initiated in acute/recent infection, followed by a decrease after treatment interruption 66 . Candida -specific lymphoproliferative responses and cytokine secreting capacity of T cells might not be congruent and it is likely that ART was initiated later than 2 w.p.i.…”

Functional Profile of CD8+ T-Cells in Response to HLA-A*02:01-Restricted Mutated Epitopes Derived from the Gag Protein of Circulating HIV-1 Strains from Medellín, Colombia

“…In contrast, this improvement is also observed for Gag-specific CD8 + T-cells after 114 weeks of therapy ( 55 ). Similarly, other studies have shown that IFN-γ + HIV-specific CD8 + T-cells increase in magnitude after one year of suppressive cART ( 59 ). In line with these data, we observed a higher polyfunctional response to the mutated variants S54A and Y79F/T84V/L85F in individuals with longer treatment duration, suggesting that the quality of the CD8 + T-cells response to epitope variants may be maintained in the setting of low-level viremia induced by cART.…”