Search

The female genital tract (FGT) is an important site of human immunodeficiency virus (HIV) infection. Discerning the nature of HIV-specific local immune responses is crucial for identifying correlates of protection in HIV-exposed seronegative (HESN) individuals. The present study involved a comprehensive analysis of soluble immune mediators, secretory immunoglobulins (sIg), natural killer (NK) cells, CXCR5+ CD8+ T cells, T follicular helper (Tfh) cells, and T regulatory cells (Tregs) in the vaginal mucosa as well as the nature and composition of the cervicovaginal microbiome in HESN women. We found significantly elevated antiviral cytokines, soluble immunoglobulins, and increased frequencies of activated NK cells, CXCR5+ CD8+ T cells, and Tfh cells in HESN females compared to HIV-unexposed healthy (UH) women. Analysis of the genital microbiome of HESN women revealed a greater bacterial diversity and increased abundance of Gardnerella spp. in the mucosa. The findings suggest that the female genital tract of HESN females represents a microenvironment equipped with innate immune factors, antiviral mediators, and critical T cell subsets that protect against HIV infection. IMPORTANCE The vast majority of human immunodeficiency virus (HIV) infections across the world occur via the sexual route. The genital tract mucosa is thus the primary site of HIV replication, and discerning the nature of HIV-specific immune responses in this compartment is crucial. The role of the innate immune system at the mucosal level in exposed seronegative individuals and other HIV controllers remains largely unexplored. This understanding can provide valuable insights to improve vaccine design. We investigated mucosal T follicular helper (Tfh) cells, CXCR5+ CD8+ T cells, natural killer (NK) cells subsets, soluble immune markers, and microbiome diversity in HIV-exposed seronegative (HESN) women. We found a significantly higher level of mucosal CXCR5+ CD8+ T cells, CD4+ Tfh cells, activated NK cell subsets, and antiviral immune cell mediators in HESN women. We also found a higher abundance of Gardnerella spp., microbiome dysbiosis, and decreased levels of inflammatory markers to be associated with reduced susceptibility to HIV infection. Our findings indicate that increased distribution of mucosal NK cells, CXCR5+ CD8+ T cells, Tfh cells, and soluble markers in HIV controllers with a highly diverse cervicovaginal microbiome could contribute effectively to protection against HIV infection. Overall, our findings imply that future vaccine design should emphasize inducing these highly functional cell types at the mucosal sites.

Objective: To study the prevalence of low‐level viraemia (LLV) and its association with virological failure (VF). Methods: We conducted a retrospective analysis of 3498 participants at YRG CARE, Chennai, India (2013–2018) on antiretroviral therapy (ART) for ≥6 months with two or more plasma viral load (pVL) measurements. Results were stratified for those with pVL <1000 copies/mL: fully suppressed (FS) (pVL <40), low‐LLV (pVL 40–199), mid‐LLV (pVL 200–399), and high‐LLV (pVL 400–999). The study assessed the association with VF (pVL >1000 copies/mL) using Cox proportional hazard model. Results: Among 3498 participants, 2965 (84.8%) were FS and 533 (15.2%) were LLV. During the follow‐up, 348 (10%) experienced VF, with 222 (6.3%) experienced after LLV (42% of LLV) and 126 (3.6%) experienced after FS (4.3% of FS). When compared with FS, those with LLV had a greater risk of VF [adjusted hazard ratio (aHR) = 12.7; 95% confidence interval (CI): 10.2–15.9]. First‐line participants had a higher VF incidence (aHR = 15.8, 95% CI: 11.4–21.9) than second‐line participants (aHR = 5.6, 95% CI: 4.1–7.7). Those with high‐LLV had the highest VF risk (aHR = 22.856, 95% CI: 15.204–34.359 vs. aHR = 8.186, 95% CI: 5.564–12.043, for first‐line vs. second‐line participants, respectively), followed by those with mid‐LLV (aHR = 13.375, 95% CI: 8.327–21.483 vs. aHR = 6.261, 95% CI: 4.044–9.695) and low‐LLV (aHR = 12.976, 95% CI: 7.974–21.118 vs. aHR = 4.158, 95% CI: 2.826–6.119). Conclusions: The prevalence of LLV was intermediate in our study population. There was a higher risk of VF among individuals with LLV, and this risk increased with the increasing levels of LLV. Close monitoring of individuals experiencing LLV could help in the early identification of VF. [ABSTRACT FROM AUTHOR]

HIV-specific CD8+ T cells are known to play a key role in viral control during acute and chronic HIV infection. Although many studies have demonstrated the importance of HIV-specific CD8+ T cells in viral control, its correlation with protection against HIV infection remains incompletely understood. To better understand the nature of the immune response that contributes to the early control of HIV infection, we analyzed the phenotype, distribution and function of anti-viral CD8+ T cells in a cohort of HIV-exposed seronegative (HESN) women, and compared them with healthy controls and HIV-infected individuals. Further, we evaluated the in vitro viral inhibition activity of CD8+ T cells against diverse HIV-1 strains. We found that the HESN group had significantly higher levels of CD8+ T cells that express T-stem cell-like (TSCM) and follicular homing (CXCR5+) phenotype with more effector like characteristics as compared to healthy controls. Further, we observed that the HESN population had a higher frequency of HIV-specific poly-functional CD8+ T cells with robust in vitro virus inhibiting capacity against different clades of HIV. Overall, our results demonstrate that the HESN population has elevated levels of HIV-specific poly-functional CD8+ T cells with robust virus inhibiting ability and express elevated levels of markers pertaining to TSCM and follicular homing phenotype. These results demonstrate that future vaccine and therapeutic strategies should focus on eliciting these critical CD8+ T cell subsets. [ABSTRACT FROM AUTHOR]

Background: Ritonavir‑boosted atazanavir (ATV/r) is the preferred second‑line protease inhibitor (PI) option for HIV patients in resource‑limited settings; its pattern of adverse drug reactions (ADRs) has not been much reported from India; hence, in this study, we have analyzed the incidence of ATV/r‑associated ADRs in Southern Indian HIV‑1‑infected patients. Methods: In this prospective study, 111 HIV patients treated with ATV/r were included with at least 2 years follow‑up visits for the emergence of hyperbilirubinemia, hypertransaminasemia, and serum creatinine elevation. The causality assessment was done based on the WHO scale for the causality assessment of suspected ADR. Results: The incidence of severe hyperbilirubinemia, hypertransaminasemia, and creatinine elevation was 28.6, 0.76, and 1.62 cases/100 person years, respectively. 3TC/FTC + TDF (odds ratio [OR]: 6.07, confidence interval [CI]: 1.31–27.98, P = 0.015) nucleos (t) ide reverse transcriptase inhibitor backbone and male sex (OR: 18.64, CI: 2.13–162.93, P = 0.0082) were found to be significantly associated with hypertransaminasemia and creatinine elevation, respectively. The causality assessment of ADR was “possible” for all the participants. Kaplan–Meier analysis showed hyperbilirubinemia to emerge earlier (mean duration: 32.18 months, CI: 24.9–39.4 months) followed by hypertransaminasemia and creatinine elevation. Hyperbilirubinemia is an expected side effect associated with ATV/r which is benign, transient, and does not predispose to hypertransaminasemia. Conclusion: Our study results show that patients starting ATV/r should be counseled for a good adherence in spite of the emergence of hyperbilirubinemia which generally reverts to normal range. [ABSTRACT FROM AUTHOR]

HIV-specific CD8 + T cells are known to play a key role in viral control during acute and chronic HIV infection. Although many studies have demonstrated the importance of HIV-specific CD8 + T cells in viral control, its correlation with protection against HIV infection remains incompletely understood. To better understand the nature of the immune response that contributes to the early control of HIV infection, we analyzed the phenotype, distribution and function of anti-viral CD8 + T cells in a cohort of HIV-exposed seronegative (HESN) women, and compared them with healthy controls and HIV-infected individuals. Further, we evaluated the in vitro viral inhibition activity of CD8 + T cells against diverse HIV-1 strains. We found that the HESN group had significantly higher levels of CD8 + T cells that express T-stem cell-like (TSCM) and follicular homing (CXCR5 + ) phenotype with more effector like characteristics as compared to healthy controls. Further, we observed that the HESN population had a higher frequency of HIV-specific poly-functional CD8 + T cells with robust in vitro virus inhibiting capacity against different clades of HIV. Overall, our results demonstrate that the HESN population has elevated levels of HIV-specific poly-functional CD8 + T cells with robust virus inhibiting ability and express elevated levels of markers pertaining to TSCM and follicular homing phenotype. These results demonstrate that future vaccine and therapeutic strategies should focus on eliciting these critical CD8 + T cell subsets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Munusamy Ponnan, Thiruvengadam, Kathirvel, Shankar, Rajaraman, Mathaiyan, Dinesha, Poongulali, Saravanan, Murugavel, Swaminathan, Tripathy, Neogi, Velu and Hanna.)

Background & Objectives: Nucleoside reverse transcriptase inhibitors (NRTIs) are known to cause mitochondrial toxicity. This study was done to estimate mitochondrial DNA (mtDNA) content of peripheral blood mononuclear cells (PBMCs) among human immunodeficiency virus (HIV) infected, NRTI treated and antiretroviral therapy (ART)-naïve patients and evaluate the utility of mtDNA content as a biomarker of mitochondrial toxicity., Methods: mtDNA content in PBMCs of 57 HIV-infected ART untreated and 30 ART treated with stavudine (d4T) or zidovudine (AZT) containing regimen were compared against 24 low-risk healthy controls (LoRHC)., Results: There was a significant (P=0.01) reduction in mtDNA content among HIV-infected (104; 80-135) compared to LoRHC (127; 110-167), and it was the same in both the treated (104.8; 88-130) and untreated patients (104.7; 78-142). mtDNA significantly (P=0.014) declined in ART treated patients symptomatic for toxicity (97; 74-111) than the asymptomatic patients (128; 103- 153)., Interpretation & Conclusions: mtDNA depletion in PBMCs was evident among HIV-infected individuals on ART. Moreover, as mtDNA content was reduced among the patients symptomatic for toxicity than the asymptomatic in both the HIV-infected groups, the current study supports mtDNA content of PBMCs to serve as a biomarker of mitochondrial dysfunction induced by NRTI and HIV. Longitudinal studies with a large sample need to be done to confirm these findings., Competing Interests: None