The association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there is a non-reversible component of neural injury that tracks with a history of disease progression. The association of sustained impairment with worse current immune status (low CD4 cell count) suggests that restoring immunocompetence increases the likelihood of neurocognitive recovery. Finally, the lack of association between incident neurocognitive impairment and virological and immunological indicators implies that neural injury continues in some patients regardless of the success of antiretroviral therapy on these laboratory measures.

Objectives To estimate neuropathic sign/symptom rates with initiation of combination antiretroviral therapy (cART) in HIV-infected ART-naive patients, and to investigate risk factors for: peripheral neuropathy and symptomatic peripheral neuropathy (SPN), recovery from peripheral neuropathy/SPN after neurotoxic ART (nART) discontinuation, and the absence of peripheral neuropathy/SPN while on nART. Design AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trial participants who initiated cART in randomized trials for ART-naive patients were annually screened for symptoms/signs of peripheral neuropathy. ART use and disease characteristics were collected longitudinally. Methods Peripheral neuropathy was defined as at least mild loss of vibration sensation in both great toes or absent/hypoactive ankle reflexes bilaterally. SPN was defined as peripheral neuropathy and bilateral symptoms. Generalized estimating equation logistic regression was used to estimate associations. Results Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007. Rates of peripheral neuropathy/SPN at 3 years were 32.1/8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/µl. Associations with higher odds of peripheral neuropathy included older patient age and current nART use. Associations with higher odds of SPN included older patient age, nART use, and history of diabetes mellitus. Associations with lower odds of recovery after nART discontinuation included older patient age. Associations with higher odds of peripheral neuropathy while on nART included older patient age and current protease inhibitor use. Associations with higher odds of SPN while on nART included older patient age, history of diabetes, taller height, and protease inhibitor use. Conclusion Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for peripheral neuropathy/SPN.

Background Treatment initiation with integrase strand transfer inhibitors (INSTIs) has been associated with excess weight gain. Whether similar gains are seen after switch to INSTIs among virologically suppressed persons is less clear. We assessed pre/post-INSTI weight changes from AIDS Clinical Trials Group participants (A5001 and A5322). Methods Participants who were in follow-up from 1997–2017 and switched to INSTI-based antiretroviral regimens were included. Piecewise linear mixed-effects models adjusting for age, sex, race/ethnicity, baseline BMI, nadir and current CD4+ T-cell count, smoking, diabetes and follow-up time with suppressed HIV-1 RNA examined weight and waist circumference change before and after first switch to INSTIs. Linear spline models with a single knot at time of switch accounted for nonlinear trends. Results The 972 participants who switched to INSTIs were 81% male and 50% nonwhite with a median age at switch of 50 years, CD4+ T-cell count 512 cells/μL, and BMI 26.4 kg/m2. Restricting to persons with suppressed HIV-1 RNA at switch (n = 691), women, blacks, and persons ≥60 years experienced greater weight gain in the 2 years after versus before switch. In adjusted models, white or black race, age ≥60, and BMI ≥30 kg/m2 at switch were associated with greater weight gain following switch among women; age ≥60 was the greatest risk factor among men. Trends for waist circumference were similar. Conclusions Yearly weight gain increased following switch to INSTIs, particularly for women, blacks, and persons aged ≥60. Concomitant increases in waist circumference suggest that this weight gain is associated with an increase in fat mass.

Objective-Differences in antiretroviral (ARV) distribution into the central nervous system (CNS) may impact neurocognitive status. We assessed the relationship between estimates of ARV therapy penetration into the CNS, using a published ranking system, and neurocognitive status in HIV-positive subjects with plasma HIV-1 RNA (vRNA) suppression.Design-Subjects with ≥6 weeks ongoing ARV use and vRNA<50 copies/mL (N=2,636; 83% male, median baseline CD4 T-cells: 244 cells/uL) had ≥1 neuroscreen assessment (Trailmaking A,B, WAIS-R Digit Symbol) at 10,413 neurovisits. Neuroscreen test scores were demographically adjusted and converted to Z-scores (NPZ3: lower scores imply more impairment). CNS penetration-effectiveness (CPE) ranks of 0.0(low), 0.5(medium) or 1.0(high) were assigned to ARVs and summed per regimen, per neurovisit. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Role of author:Marlene Smurzynski: study and conceptual design, assisted with data analysis, interpretation of findings, wrote and edited manuscript, finalized manuscript for publication Kunling Wu: data analysis, created figures and tables, interpretation of findings, reviewed manuscript Scott Letendre: study and conceptual design, interpretation of findings, contributed to manuscript development, edited manuscript Kevin Robertson: study and conceptual design, interpretation of findings, edited manuscript Ronald J. Bosch: assisted with data analysis, interpretation of findings, edited manuscript David B. Clifford: interpretation of findings, edited manuscript Scott Evans: assisted with data analysis, interpretation of findings, reviewed manuscript Ann C. Collier: interpretation of findings, edited manuscript Michael Taylor: completed the normalized neurocognitive test scores (NPZ3 scores), reviewed manuscript Ronald Ellis: study and conceptual design, interpretation of findings, contributed to manuscript development, edited manuscript NIH Public Access Methods-Multivariate linear regression models using generalized estimating equations assessed NPZ3 scores with respect to ARV regimen. Covariates were retained if p≤0.1.Results-A final model demonstrated that better NPZ3 scores were associated with higher CPE among subjects taking >3 ARVs (+0.07 per one unit increase in CPE score; p=0.004) but not among subjects with ≤3 ARVs in the regimen (+0.01; p=0.5). Results were adjusted for demographics, injection drug use, HCV serostatus, CD4 count (current and nadir), baseline vRNA, ARV experience and years since first ARV use.Conclusions-Use of ARVs with better estimated CNS penetration may be associated wi...

Objective Both frailty and falls occur at earlier than expected ages among HIV-infected individuals, but the contribution of frailty to fall risk in this population is not well understood. We examined this association among participants enrolled in AIDS Clinical Trials Group (ACTG) A5322. Design A prospective, multi-center cohort study of HIV-infected men and women ≥40 years. Methods Frailty assessment included a 4-meter walk, grip strength, and self-reported weight loss, exhaustion, and low physical activity. Multinomial logistic regression assessed the association between baseline frailty, grip, and 4-meter walk and single and recurrent (2+) falls over the next 12 months; logistic regression assessed effect modification by several factors on association between frailty and any (1+) falls. Results Of 967 individuals, 6% were frail, 39% pre-frail, and 55% non-frail. Eighteen percent had ≥1 fall, and 7% had recurrent falls. In multivariable models, recurrent falls were more likely among frail (OR=17.3; 95% CI=7.03-42.6) and pre-frail (OR=3.80; 95% CI=1.87-7.72) than non-frail individuals. Significant associations were also seen with recurrent falls and slow walk and weak grip. The association between frailty and any falls was substantially stronger among individuals with peripheral neuropathy. Conclusions Aging HIV-infected pre-frail and frail individuals are at significantly increased risk of falls. Incorporation of frailty assessments or simple evaluations of walk speed or grip strength in clinical care may help identify individuals at greatest risk for falls. Peripheral neuropathy further increases fall risk among frail persons, defining a potential target population for closer fall surveillance, prevention, and treatment.

Polymorphisms in APOL1 are associated with CKD, including HIV-related CKD, in individuals of African ancestry. The apolipoprotein L1 (APOL1) protein circulates and is localized in kidney cells, but the contribution of APOL1 location to CKD pathogenesis is unclear. We examined associations of plasma APOL1 levels with plasma cytokine levels, dyslipidemia, and APOL1 genotype in a nested case-control study (n=270) of HIV-infected African Americans enrolled in a multicenter prospective observational study. Patients were designated as having CKD when estimated GFR (eGFR) decreased to ,60 ml/min per 1.73 m 2 (eGFR,60 cohort) or protein-to-creatinine ratios became .3.5 g/g (nephrotic proteinuria cohort).Circulating APOL1 levels did not associate with APOL1 genotype, CKD status, or levels of proinflammatory cytokines, but did correlate with fasting cholesterol, LDL cholesterol, and triglyceride levels. At ascertainment, CKD-associated polymorphisms (risk variants) in APOL1 associated with the eGFR,60 cohort, but not the nephrotic-range proteinuria cohort. Of note, in both the eGFR,60 and nephrotic proteinuria cohorts, CKD cases with two APOL1 risk variants had significant declines in eGFR over a median of 4 years compared with individuals with one or no risk variants. APOL1 risk genotype was not associated with changes in proteinuria. Higher circulating proinflammatory cytokine levels were independently associated with CKD but not APOL1 genotype. In conclusion, the function of variant APOL1 proteins derived from circulation or synthesized in the kidney, but not the level of circulating APOL1, probably mediates APOL1-associated kidney disease in HIV-infected African Americans.

Purpose-ALLRT is a longitudinal cohort study of HIV-infected subjects prospectively randomized into selected clinical trials for antiretroviral (ARV) treatment-naïve and ARV treatmentexperienced individuals conducted by the AIDS Clinical Trials Group (ACTG). We describe the rationale, design, and baseline characteristics of the ALLRT cohort and its potential to address important research questions related to ARV therapy. Method-Standardized visits occur every 16 weeks to evaluate long-term clinical, virologic, and immunologic outcomes associated with ARV treatment.Results-A total of 4,371 subjects enrolled in ALLRT from January 2000 through June 2007. Of these, 3,146 (72%) were ARV naïve at parent study entry (18% female, 44% white, 32% black, 21% Hispanic; median age 37 years, CD4 count 218 cells/μL, follow-up 3.6 years; 343 [11%] followed ≥8 years) and 1,225 (28%) were treatment experienced (13% female, 59% white, 20% black, 17% Hispanic; median age 42 years, CD4 count 325 cells/μL, follow-up 5.7 years).Conclusions-ALLRT provides the opportunity to understand long-term ramifications of therapeutic ARV choices and determine whether these vary by treatment regimen, timing of treatment initiation, or treatment changes over long-term follow-up. Investigations based on uniform data and specimen collection in the context of randomized ARV treatments will be critical to developing more successful long-term therapeutic strategies for HIV treatment. KeywordsCD4 counts; cohort studies; epidemiologic research design; HIV; randomized controlled trials; viral load Since its inception in 1987, the AIDS Clinical Trials Group (ACTG) has performed clinical trials in persons with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) focused on measuring the impact of antiretroviral (ARV) therapies, treatment strategies, prophylaxis and treatment of opportunistic complications, and immune-based interventions on HIV disease morbidity and survival. These studies have had significant influence in determining appropriate management for HIV disease and its Short-term fixed-regimen, fixed-duration comparative trials for defined patient populations are important to characterize the comparative antiviral activity of drugs and regimens and novel treatment strategies, but they often do not address long-term management questions in an efficient and generalizable manner. One approach to characterize longer term outcomes is to prospectively plan meta-analyses or cross-protocol analyses of longitudinally followed subjects who undergo standardized collection of information about treatment regimens, factors that impact treatment response, and outcomes over an extended time period. The ALLRT study provides the context in which the ACTG can examine longer term outcomes among subjects who have participated in their shorter term fixed-duration trials. METHOD Overview and Design of the ACTG Longitudinal Linked Randomized Trials (ALLRT) ProtocolThe ALLRT study (protocol A5001) is a unique prospective cohor...

G protein-coupled receptors (GPCRs) convey extracellular stimulation into dynamic intracellular action, leading to the regulation of cell migration and differentiation. T lymphocytes express G␣ i2 and G␣ i3 , two members of the G␣ i/o protein family, but whether these two G␣ i proteins have distinguishable roles guiding T cell migration remains largely unknown because of a lack of member-specific inhibitors. This study details distinct G␣ i2 and G␣ i3 effects on chemokine receptor CXCR3-mediated signaling. Our data showed that G␣ i2 was indispensable for T cell responses to three CXCR3 ligands, CXCL9, CXCL10, and CXCL11, as the lack of G␣ i2 abolished CXCR3-stimulated migration and guanosine 5-3-O-(thio)triphosphate (GTP␥S) incorporation. In sharp contrast, T cells isolated from G␣ i3 knock-out mice displayed a significant increase in both GTP␥S incorporation and migration as compared with wild type T cells when stimulated with CXCR3 agonists. The increased GTP␥S incorporation was blocked by G␣ i3 protein in a dose-dependent manner. G␣ i3 -mediated blockade of G␣ i2 activation did not result from G␣ i3 activation, but instead resulted from competition or steric hindrance of G␣ i2 interaction with the CXCR3 receptor via the N terminus of the second intracellular loop. A mutation in this domain abrogated not only G␣ i2 activation induced by a CXCR3 agonist but also the interaction of G␣ i3 to the CXCR3 receptor. These findings reveal for the first time an interplay of G␣ i proteins in transmitting G protein-coupled receptor signals. This interplay has heretofore been masked by the use of pertussis toxin, a broad inhibitor of the G␣ i/o protein family.Heterotrimeric G proteins consist of ␣, ␤, and ␥ subunits that couple to seven transmembrane receptors called G proteincoupled receptors (GPCRs).3 The G protein resides attached to the intracellular face of the plasma membrane in an inactive form consisting of the G␣ subunit bound to GDP, a structure that is stabilized by interaction with the ␤␥ dimer. Agonist binding to the receptor provokes a conformation change that facilitates the interaction of the G␣ subunit to the receptor. Upon interaction with the receptor, G␣ protein becomes activated, causing GDP exchange for GTP. This activation to the high energy G␣-GTP results in dissociation of the ␣ and ␤␥ subunits and propagation of downstream signaling by both the G␣-GTP and the ␤␥ subunits. The GTP-binding proteins are classified by the signaling events they instigate, of which there are four major families as follows: G␣ i/o , G␣ q/11 , G␣ 12/13 , and G␣ s (1, 2). Members of the G␣ i/o family, including G␣ i1 , G␣ i2 , G␣ i3 , G␣ o , G␣ gust , and G␣ t , can all be irreversibly uncoupled from receptors by pertussis toxin (PTX) (3, 4). PTX catalyzes ADP-ribosylation of a specific cysteine residue at position Ϫ4 from the C terminus of the ␣ subunits, and thus blocks downstream pathways by preventing receptor interaction (5). The bacterial toxin has proven to be an excellent tool in dissecting the essential role of G␣...