A set of mutations [Ala-62 -> Val(A62V), V75I, F77L, F116Y, and Q151M] in the polymerase domain of reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) confers on the virus a reduced sensitivity to multiple antiretroviral dideoxynucleosides and has been seen in HIV-1 variants isolated from patients receiving combination chemotherapy with 3'-azido-3'-deoxythymidine (AZT) plus 2',3'-dideoxycytidine (ddC) or 2',3'-dideoxyinosine (ddl). The IC50 values of AZT, ddC, ddI, 2',3'-dideoxyguanosine, and 2',3'-didehydro-3'-deoxythymidine against an infectious clone constructed to include the five mutations were significantly higher than those of a wild-type infectious clone. The Ki value for AZT 5'-triphosphate determined for the virus-associated RT from a posttherapy strain was 35-fold higher than that of RT from a pretherapy strain. Detailed analysis of HIV-1 strains isolated at various times during therapy showed that the Q151M mutation developed first in vivo, at the time when the viremia level suddenly increased, followed by the F116Y and F77L mutations. All five mutations ultimately developed, and the viremia level rose even further. Analyses based on the three-dimensional structure of HIV-1 RT suggest that the positions where at least several of the five mutations occur are located in close proximity to the proposed dNTP-binding site of RT and the first nucleotide position of the single-stranded template.

BackgroundAging and HIV infection are independently associated with excessive immune activation and impaired immune responses to vaccines, but their relationships have not been examined.MethodsFor selecting an aging population we enrolled 28 post-menopausal women including 12 healthy volunteers and 16 HIV-infected women on antiretroviral treatment with <100 HIV RNA copies/ml. Antibody titers to trivalent influenza vaccination given during the 2011-2012 season were determined before and 4 weeks after vaccination.ResultsSeroprotective influenza antibody titers (≥1:40) were observed in 31% HIV+ and 58% HIV-uninfected women pre-vaccination. Following vaccination, magnitude of antibody responses and frequency of seroprotection were lower in HIV+ (75%) than in HIV– (91%) women. Plasma IL-21, the signature cytokine of T follicular helper cells (Tfh), and CD4 T cell IL-21R were upregulated with seroconversion (≥4 fold increase in antibody titer). Post-vaccine antibody responses were inversely correlated with pre-vaccination plasma TNFα levels and with activated CD4 T cells, including activated peripheral (p)Tfh. Plasma TNFα levels were correlated with activated pTfh cells (r=0.48, p=0.02), and inversely with the post-vaccination levels of plasma IL-21 (r=-0.53, p=0.02). In vitro TNFα blockade improved the ability of CD4 T cells to produce IL-21 and of B cells to secrete immunoglobulins, and addition of exogenous IL-21 to cell cultures enhanced B cell function. Higher frequencies of activated and exhausted CD8 T and B cells were noted in HIV+ women, but these markers did not show a correlation with antibody responses.ConclusionsIn aging HIV-infected and uninfected women, activated CD4 and pTfh cells may compromise influenza vaccine-induced antibody response, for which a mechanism of TNFα-mediated impairment of pTfh-induced IL-21 secretion is postulated. Interventions aimed at reducing chronic inflammation and immune activation in aging, HIV-infected patients may improve their response to vaccines.

Background: The spread of severe acute respiratory syndrome coronavirus 2, causative agent of the coronavirus disease 2019 (COVID-19), has necessitated widespread lockdown to mitigate the pandemic. This study examines the influence of resilience on the impact of COVID-related stress and enforced lockdown on mental health, drug use, and treatment adherence among people living with HIV (PLWH) in Argentina. Setting: PLWH residing predominantly in Buenos Aires Metropolitan Area and urban regions of Argentina were identified from a private clinic electronic database. Methods: Participants completed an anonymous online survey to evaluate the impact of COVID-19 on economic disruption, resilience, mental health outcomes (depression, anxiety, stress, and loneliness), adherence to HIV treatment, and substance use. We performed ordinary least squares and logistic regressions to test whether resilient coping buffered the impact of economic disruption on mental health and drug use during quarantine. Results: A total of 1336 PLWH aged 18–82 were enrolled. The impact of economic disruption on mental health ΔF(1,1321) = 8.86, P = 0.003 and loneliness ΔF(1,1326) = 5.77, P = 0.016 was buffered by resilience. A 3-way interaction between resilient buffering, stress, and sex was significant ΔF(1,1325) = 4.76, P = 0.029. Participants reported less than excellent adherence to medication (33%), disruption to mental health services (11%), and disruption to substance abuse treatment (1.3%) during lockdown. Discussion: The impact of COVID-stress and lockdown on emotional distress seemed mitigated by resilience coping strategies, and the buffering impact of resilience on perceived stress was greater among women. Results highlight PLWH's capacity to adhere to treatment in challenging circumstances and the importance of developing resilience skills for better coping with stress and adversity.

Immune activation associated with HIV infection and impaired pTfh function heighten deficiencies in antibody responses to influenza vaccine in older individuals. Strategies to reduce immune activation or augment pTfh function may enhance antibody responses in the aging HIV-infected population.

BackgroundPersistent immune activation and microbial translocation associated with HIV infection likely place HIV-infected aging women at high risk of developing chronic age-related diseases. We investigated immune activation and microbial translocation in HIV-infected aging women in the post-menopausal ages.MethodsTwenty-seven post-menopausal women with HIV infection receiving antiretroviral treatment with documented viral suppression and 15 HIV-negative age-matched controls were enrolled. Levels of immune activation markers (T cell immune phenotype, sCD25, sCD14, sCD163), microbial translocation (LPS) and biomarkers of cardiovascular disease and impaired cognitive function (sVCAM-1, sICAM-1 and CXCL10) were evaluated.ResultsT cell activation and exhaustion, monocyte/macrophage activation, and microbial translocation were significantly higher in HIV-infected women when compared to uninfected controls. Microbial translocation correlated with T cell and monocyte/macrophage activation. Biomarkers of cardiovascular disease and impaired cognition were elevated in women with HIV infection and correlated with immune activation.ConclusionsHIV-infected antiretroviral-treated aging women who achieved viral suppression are in a generalized status of immune activation and therefore are at an increased risk of age-associated end-organ diseases compared to uninfected age-matched controls.