To evaluate whether penetration of a combination regimen into the central nervous system (CNS), as estimated by the CNS Penetration-Effectiveness (CPE) rank, is associated with lower cerebrospinal fluid (CSF) viral load. Design: Data were analyzed from 467 participants who were human immunodeficiency virus (HIV) seropositive and who reported antiretroviral (ARV) drug use. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high) based on their chemical properties, concentrations in CSF, and/or effectiveness in the CNS in clinical studies. The CPE rank was calculated by summing the individual penetration ranks for each ARV in the regimen. Results: The median CPE rank was 1.5 (interquartile range, 1-2). Lower CPE ranks correlated with higher CSF viral loads. Ranks less than 2 were associated with an 88% increase in the odds of detectable CSF viral load. In multivariate regression, lower CPE ranks were associated with detectable CSF viral loads even after adjusting for total number of ARV drugs, ARV drug adherence, plasma viral load, duration and type of the current regimen, and CD4 count. Conclusions: Poorer penetration of ARV drugs into the CNS appears to allow continued HIV replication in the CNS as indicated by higher CSF HIV viral loads. Because inhibition of HIV replication in the CNS is probably critical in treating patients who have HIVassociated neurocognitive disorders, ARV treatment strategies that account for CNS penetration should be considered in consensus treatment guidelines and validated in clinical studies.
HIV can infect the brain and impair central nervous system (CNS) function. Combination antiretroviral therapy (cART) has not eradicated CNS complications. HIV-associated neurocognitive disorders (HAND) remain common despite cART, although attenuated in severity. This may result from a combination of factors including inadequate treatment of HIV reservoirs such as circulating monocytes and glia, decreased effectiveness of cART in CNS, concurrent illnesses, stimulant use, and factors associated with prescribed drugs, including antiretrovirals. This review highlights recent investigations of HIV-related CNS injury with emphasis on cART-era neuropathological mechanisms in the context of both US and international settings.
We investigated interactions between HIV and aging on brain function demands using functional magnetic resonance imaging (fMRI). A multiple regression model studied the association and interaction between fMRI measures, HIV serostatus, and age for 26 HIV infected (HIV+) and 25 seronegative (HIV−) subjects. While HIV serostatus and age independently affected fMRI measures, no interaction occurred. Functional brain demands in HIV+ subjects were equivalent to ~15–20 year older HIV− subjects. Frailty parallels between HIV and aging could result from continued immunological challenges depleting resources and triggering increased metabolic demands. fMRI could be a non-invasive biomarker to assess HIV in the brain.
Background The risk of severe COVID-19 varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). Objective To examine whether deficits in IR that antedate or are induced by SARS-CoV-2 infection independently predict COVID-19 mortality. Methods IR levels were quantified with two novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort ( n =522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts ( n =13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to clinical outcomes. Results IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection associated with underrepresentation of IHG-I (21%) vs. overrepresentation (77%) of IHG-II or IHG-IV, especially in males vs. females ( P <0.01). Presentation with IHG-I associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. Conclusion Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19. Clinical implications Biomarkers tracking immunologic resilience may have broad prognostic utility, as they associated with longevity, as well as resistance to a progressive disease course during SARS-CoV-2, influenza, or HIV infection.
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