The HIV-1 late domain-2 S40A polymorphism in antiretroviral (or ART)-exposed individuals influences protease inhibitor susceptibility.

BackgroundThe p6 region of the HIV-1 structural precursor polyprotein, Gag, contains two motifs, P7TAP11 and L35YPLXSL41, designated as late (L) domain-1 and -2, respectively. These motifs bind the ESCRT-I factor Tsg101 and the ESCRT adaptor Alix, respectively, and are critical for efficient budding of virus particles from the plasma membrane. L domain-2 is thought to be functionally redundant to PTAP. To identify possible other functions of L domain-2, we examined this motif in dominant viruses that emerged in a group of 14 women who had detectable levels of HIV-1 in both plasma and genital tract despite a history of current or previous antiretroviral therapy.ResultsRemarkably, variants possessing mutations or rare polymorphisms in the highly conserved L domain-2 were identified in seven of these women. A mutation in a conserved residue (S40A) that does not reduce Gag interaction with Alix and therefore did not reduce budding efficiency was further investigated. This mutation causes a simultaneous change in the Pol reading frame but exhibits little deficiency in Gag processing and virion maturation. Whether introduced into the HIV-1 NL4-3 strain genome or a model protease (PR) precursor, S40A reduced production of mature PR. This same mutation also led to high level detection of two extended forms of PR that were fairly stable compared to the WT in the presence of IDV at various concentrations; one of the extended forms was effective in trans processing even at micromolar IDV.ConclusionsOur results indicate that L domain-2, considered redundant in vitro, can undergo mutations in vivo that significantly alter PR function. These may contribute fitness benefits in both the absence and presence of PR inhibitor

Characteristics of HIV-infected Children at Enrollment Into Care and at Antiretroviral Therapy Initiation in Central Africa

BACKGROUND: Despite the World Health Organization (WHO) regularly updating guidelines to recommend earlier initiation of antiretroviral therapy (ART) in children, timely enrollment into care and initiation of ART in sub-Saharan Africa in children lags behind that of adults. The impact of implementing increasingly less restrictive ART guidelines on ART initiation in Central Africa has not been described. MATERIALS AND METHODS: Data are from the Central Africa International Epidemiologic Databases to Evaluate AIDS (IeDEA) pediatric cohort of 3,426 children (0-15 years) entering HIV care at 15 sites in Burundi, DRC, and Rwanda. Measures include CD4 count, WHO clinical stage, age, and weight-for-age Z score (WAZ), each at enrollment into HIV care and at ART initiation. Changes in the medians or proportions of each measure by year of enrollment and year of ART initiation were assessed to capture potential impacts of changing ART guidelines. RESULTS: Median age at care enrollment decreased from 77.2 months in 2004-05 to 30.3 months in 2012-13. The median age at ART initiation (n = 2058) decreased from 83.0 months in 2004-05 to 66.9 months in 2012-13. The proportion of childre

Characteristics of HIV-Infected Children at Enrollment into Care and at Antiretroviral Therapy Initiation in Central Africa

Background Despite the World Health Organization (WHO) regularly updating guidelines to recommend earlier initiation of antiretroviral therapy (ART) in children, timely enrollment into care and initiation of ART in sub-Saharan Africa in children lags behind that of adults. The impact of implementing increasingly less restrictive ART guidelines on ART initiation in Central Africa has not been described. Materials and Methods Data are from the Central Africa International Epidemiologic Databases to Evaluate AIDS (IeDEA) pediatric cohort of 3,426 children (0±15 years) entering HIV care at 15 sites in Burundi, DRC, and Rwanda. Measures include CD4 count, WHO clinical stage, age, and weight-for-age Z score (WAZ), each at enrollment into HIV care and at ART initiation. Changes in the medians or proportions of each measure by year of enrollment and year of ART initiation were assessed to capture potential impacts of changing ART guidelines. Results Median age at care enrollment decreased from 77.2 months in 2004±05 to 30.3 months in 2012±13. The median age at ART initiation (n = 2058) decreased from 83.0 months in 2004±05 to 66.9 months in 2012±13. The proportion of children 24 months of age at enrollment increased from 12.7% in 2004±05 to 46.7% in 2012±13, and from 9.6% in 2004±05 to 24.2% in 2012±13 for ART initiation. The median CD4 count at enrollment into care increased from 563 (IQR: 275, 901) in 2004±05 to 660 (IQR: 339, 1071) cells/μl in 2012±13, and the median CD4 count at ART initiation increased from 310 (IQR:167, 600) in 2004±05 to 589 (IQR: 315, 1113) cells/μl in 2012±13. From 2004±05 to 2012±13, median WAZ improved from -2 (IQR: -3.4, -1.1) to -1 (IQR: -2.5, -0.2) at enrollment in care and from -2 (IQR: -3.8, -1.6) to -1 (IQR: -2.6, -0.4) at ART initiation. Discussion and Conclusion Although HIV-infected children 24 months of age accounted for half of all children enrolling in care in our cohort during 2012±13, they represented less than a quarter of all those who were initiated on ART during the same period. Further research is needed to identify barriers to timely diagnosis, linkage to care, and initiation of ART among children with HIV infection

Do HIV-Positive Women Receive Depression Treatment that Meets Best Practice Guidelines?

This study addressed whether psychopharmacologic and psychotherapeutic treatment of depressed HIV+ women met standards defined in the best practice literature, and tested hypothesized predictors of standard-concordant care. 1,352 HIV-positive women in the multi-center Women\u27s Interagency HIV Study were queried about depressive symptoms and mental health service utilization using standards published by the American Psychiatric Association and the Agency for Healthcare Research and Quality to define adequate depression treatment. We identified those who: (1) reported clinically significant depressive symptoms (CSDS) using Centers for Epidemiological Studies-Depression Scale scores of a parts per thousand yen16; or (2) had lifetime diagnoses of major depressive disorder (MDD) assessed by World Mental Health Composite International Diagnostic Interviews plus concurrent elevated depressive symptoms in the past 12 months. Adequate treatment prevalence was 46.2 % (n = 84) for MDD and 37.9 % (n = 211) for CSDS. Multivariable logistic regression analysis found that adequate treatment was more likely among women who saw the same primary care provider consistently, who had poorer self-rated role functioning, who paid out-of-pocket for healthcare, and who were not African American or Hispanic/Latina. This suggests that adequate depression treatment may be increased by promoting healthcare provider continuity, outreaching individuals with lower levels of reported role impairment, and addressing the specific needs and concerns of African American and Hispanic/Latina women

The relation of plasmacytoid dendritic cells (pDCs) and regulatory t-cells (Tregs) with HPV persistence in HIV-Infected and HIV-Uninfected women

Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted

Risk Factors for Cervical Precancer and Cancer in HIV-Infected, HPV-Positive Rwandan Women

Background: Although cervical cancer is an AIDS-defining condition, infection with human immunodeficiency virus (HIV) may only modestly increase the risk of cervical cancer. There is a paucity of information regarding factors that influence the natural history of human papillomavirus (HPV) in HIV-infected women. We examined factors associated with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in Rwandan women infected with both HIV and HPV (HIV+/HPV+).Methods: In 2005, 710 HIV+ Rwandan women ≥25 years enrolled in an observational cohort study; 476 (67%) tested HPV+. Each woman provided sociodemographic data, CD4 count, a cervical cytology specimen and cervicovaginal lavage (CVL), which was tested for >40 HPV genotypes by MY09/MY11 PCR assay. Logistic regression models calculated odds ratios (OR) and 95% confidence intervals (CI) of associations of potential risk factors for CIN3+ among HIV+/HPV+ women.Results: Of the 476 HIV+/HPV+ women 42 (8.8%) were diagnosed with CIN3+. Factors associated with CIN3+ included ≥7 (vs. 0-2) pregnancies, malarial infection in the previous six months (vs. never), and ≥7 (vs. 0-2) lifetime sexual partners. Compared to women infected by non-HPV16 carcinogenic HPV genotypes, HPV16 infection was positively associated and non-carcinogenic HPV infection was inversely associated with CIN3+. CD4 count was significantly associated with CIN3+ only in analyses of women with non-HPV16 carcinogenic HPV (OR = 0.62 per 100 cells/mm3, CI = 0.40-0.97).Conclusions: In this HIV+/HPV+ population, lower CD4 was significantly associated with CIN3+ only in women infected with carcinogenic non-HPV16. We found a trend for higher risk of CIN3+ in HIV+ women reporting recent malarial infection; this association should be investigated in a larger group of HIV+/HPV+ women.</p

Comparison of antibodies that mediate HIV type 1 gp120 antibody-dependent cell-mediated cytotoxicity in asymptomatic HIV type 1-positive men and women

Recent studies suggest that HIV-specific antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies contribute to protective immunity against HIV. An important characteristic of future HIV vaccines will, therefore, be the ability to stimulate production of these antibodies in both men and women. Early studies suggest that men may have a better ADCC antibody response against HIV than women. Our objective was to determine whether men and women differ with respect to their ADCC response to HIV-1 gp120. HIV-positive, asymptomatic untreated men and women were matched for race, age, CD4(+) T cell number, HIV-1 viral load, and treatment and HIV-1 gp120 ADCC antibody titers were compared. A standard (51)Cr-release assay was used to determine HIV-1 gp120 ADCC antibody titers in HIV-1-seropositive individuals from the Multicenter AIDS Cohort Study (MACS; n=32) and the Women's Interagency HIV Study (WIHS; n=32). Both sexes had high ADCC titers against HIV-1 gp120: 34.4% (n=11) and 40.6% (n=13) of men and women, respectively, had titers of 10,000; 62.5% (n=20) and 56.3% (n=18) had titers of 100,000. Groups did not differ in percent specific release (% SR), lytic units (LU), correlations of titer to viral load, or titer to CD4(+) T cells in men or women. Both groups also had similar cross-clade ADCC antibody responses (p>0.5 for % SR and LU). Comparable groups of asymptomatic HIV-1-infected men and women had comparable HIV-1 gp120 ADCC antibodies. Both sexes had significant cross-clade reactivity. Differences between men and women may become evident as disease progresses; this should be evaluated at later stages of HIV-1 infection

Cognitive changes during the menopausal transition: a longitudinal study in women with and without HIV

OBJECTIVE: To assess longitudinal changes in cognitive performance across menopause stages in a sample comprised primarily of low-income women of color, including women with HIV (WWH). METHODS: A total of 443 women (291 WWH; 69% African American; 18% Hispanic; median age = 42 y) from the Women's Interagency HIV Study completed tests of verbal learning and memory, attention/working memory, processing speed, verbal fluency, motor skills, and executive function first at an index premenopausal visit and thereafter once every 2 years for up to six visits (mean follow-up = 5.7 y). General linear-mixed effects regression models were run to estimate associations between menopause stages and cognition, in the overall sample and in WWH. We examined both continuous scores and categorical scores of cognitive impairment (yes/no >1 standard deviation below the mean). RESULTS: Adjusting for age and relevant covariates, the overall sample and WWH showed longitudinal declines in continuous measures of learning, memory, and attention/working memory domains from the premenopause to the early perimenopause and from the premenopause to the postmenopause, Ps < 0.05 to < 0.001. Effects on those same domains were also evident in categorical scores of cognitive impairment, with the increased odds of impairment ranging from 41% to 215%, Ps < 0.05 to < 0.001. The increase in predicted probability of impairment by menopausal stage (% affected) ranged from 4% to 13%. CONCLUSIONS: Menopause stage was a key determinant of cognition in a sample of low-income women of color, including WWH. Many of these changes reached a clinically significant level of cognitive impairment

Age-varying Associations of Depressive Symptoms and Heavy Episodic Drinking Throughout Adulthood Among People with HIV and Receiving care in Cameroon Within a National “treat all” Policy

Comorbid depression and heavy episodic drinking (HED) may threaten the success of “treat all” policies in sub-Saharan Africa as the population of people with HIV (PWH) ages. We investigated associations between depressive symptoms and heavy episodic drinking (HED) and the extent the relationship differed across ages among PWH receiving HIV care in Cameroon. We conducted a retrospective analysis of 18-60-year-old PWH on antiretroviral therapy in Cameroon from January 2016 to March 2020. Age-varying effect modelling was conducted to assess associations between depressive symptoms and HED across ages and by gender. Prevalence of depression and HED was highest at ages 20 and 25, respectively. After age 25, the magnitude of the association between depressive symptoms and HED was significant and increased until age 30 (aOR: 1.88, 95% CI: 1.48, 2.39), with associations remaining significant until age 55 (aOR: 1.64, 95% CI: 1.17, 2.29). Women had more variability and higher magnitudes of associations between depressive symptoms and HED than men. The interrelationship between depressive symptoms and HED was significant throughout most of adulthood for PWH receiving HIV care in Cameroon. Understanding age and gender trends in these associations can guide integration efforts in HIV care settings

Prevalence of potentially traumatic events and symptoms of depression, anxiety, hazardous alcohol use, and post-traumatic stress disorder among people with HIV initiating HIV care in Cameroon

Background: This study explored the relationship between specific types of potentially traumatic events (PTEs) and symptoms of mental health disorders among people with HIV (PWH) in Cameroon. Methods: We conducted a cross-sectional study with 426 PWH in Cameroon between 2019–2020. Multivariable log binominal regression was used to estimate the association between exposure (yes/no) to six distinct types of PTE and symptoms of depression (Patient Health Questionnaire-9 score > 9), PTSD (PTSD Checklist for DSM-5 score > 30), anxiety (Generalized Anxiety Disorder-7 scale score > 9), and hazardous alcohol use (Alcohol Use Disorders Identification Test score > 7 for men; > 6 for women). Results: A majority of study participants (96%) reported exposure to at least one PTE, with a median of 4 PTEs (interquartile range: 2–5). The most commonly reported PTEs were seeing someone seriously injured or killed (45%), family members hitting or harming one another as a child (43%), physical assault or abuse from an intimate partner (42%) and witnessing physical assault or abuse (41%). In multivariable analyses, the prevalence of PTSD symptoms was significantly higher among those who reported experiencing PTEs during childhood, violent PTEs during adulthood, and the death of a child. The prevalence of anxiety symptoms was significantly higher among those who reported experiencing both PTEs during childhood and violent PTEs during adulthood. No significant positive associations were observed between specific PTEs explored and symptoms of depression or hazardous alcohol use after adjustment. Conclusions: PTEs were common among this sample of PWH in Cameroon and associated with PTSD and anxiety symptoms. Research is needed to foster primary prevention of PTEs and to address the mental health sequelae of PTEs among PWH