Impaired Nef function is associated with early control of HIV-1 viremia.

UNLABELLED: Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P<0.01). HLA class I downregulation activity correlated inversely with days postinfection (Spearman's R=-0.85, P=0.004) and positively with baseline plasma viral load (Spearman's R=0.81, P=0.007) in acute controllers but not in acute progressors. Nef polymorphisms associated with functional changes over time were identified in follow-up samples from six controllers. For one such individual, mutational analyses indicated that four polymorphisms selected by HLA-A*31 and B*37 acted in combination to reduce Nef steady-state protein levels and HLA class I downregulation activity. Our results demonstrate that relative control of initial HIV-1 viremia is associated with Nef clones that display reduced function, which in turn may influence the course of HIV-1 infection. Transmission of impaired Nef sequences likely contributed in part to this observation; however, accumulation of HLA-associated polymorphisms in Nef that impair function also suggests that CD8+ T-cell pressures play a role in this phenomenon. IMPORTANCE: Rare individuals can spontaneously control HIV-1 viremia in the absence of antiretroviral treatment. Understanding the host and viral factors that contribute to the controller phenotype may identify new strategies to design effective vaccines or therapeutics. The HIV-1 Nef protein enhances viral pathogenesis through multiple mechanisms. We examined the function of plasma HIV-1 RNA-derived Nef clones isolated from 10 recently infected individuals who subsequently controlled HIV viremia compared to the function of those from 50 individuals who failed to control viremia. Our results demonstrate that early Nef clones from HIV controllers displayed lower HLA class I and CD4 downregulation activity, as well as a reduced ability to enhance virion infectivity. The accumulation of HLA-associated polymorphisms in Nef during the first year postinfection was associated with impaired protein function in some controllers. This report highlights the potential for host immune responses to modulate HIV pathogenicity and disease outcome by targeting cytotoxic T lymphocyte (CTL) epitopes in Nef.

Social and Structural Barriers to Primary Care Access Among Women Living With HIV in Metro Vancouver, Canada: A Longitudinal Cohort Study.

ABSTRACT: This study examines correlates of being unable to access primary care in the past 6 months among cisgender (cis) and trans women living with HIV (WLWH). Data were drawn from a longitudinal community-based cohort study of WLWH (ages 14+) in Metro Vancouver, Canada (2014-2017). Of 291 participants contributing 914 observations, 15.5% reported being unable to access primary care at baseline. In multivariable analysis, increased odds of being unable to access primary care was associated with (a) having im/migrated to Canada, and, in the past 6 months, (b) identifying as gender minority, (c) experiencing physical or sexual violence, (d) having suicidal ideation or attempts. Decreased odds were associated with recently accessing HIV-specific resources. Our findings suggest that primary health care for WLWH should address high levels of violence and mental health conditions as well as barriers to services for gender minority and im/migrant WLWH.

The impact of cystic fibrosis-related diabetes on health-related quality of life.

Cystic fibrosis-related diabetes (CFRD) is a well-known comorbidity among the CF population. To investigate whether CFRD impacts health-related quality of life (HRQoL), domain scores from the Cystic Fibrosis Questionnaire-Revised for adolescents and adults over 14 years old (CFQ-R 14+) were compared between CF individuals with CFRD on insulin, CFRD not on insulin, impaired glucose tolerance, and normal blood glucose tolerance. The median score for the Treatment Burden domain was significantly worse for individuals with CFRD on insulin (p < 0.001) compared to the other diagnostic groups, and this association remained significant following adjustment for confounding variables. In conclusion, the additional requirement for insulin significantly contributes to treatment burden in adults with CFRD and therefore novel strategies to reduce treatment burden for this group are urgently needed.