To date, the most effective treatment of HIV-1 is a combination antiretroviral therapy (cART), which reduces viral replication and reverses pathology. We investigated the effect of cART (RT and protease inhibitors) on the content of extracellular vesicles (EVs) released from HIV-1-infected cells. We have previously shown that EVs contain non-coding HIV-1 RNA, which can elicit responses in recipient cells. In this manuscript, we show that TAR RNA levels demonstrate little change with the addition of cART treatment in cell lines, primary macrophages, and patient biofluids. We determined possible mechanisms involved in the selective packaging of HIV-1 RNA into EVs, specifically an increase in EV-associated hnRNP A2/B1. More recent experiments have shown that several other FDA-approved drugs have the ability to alter the content of exosomes released from HIV-1-infected cells. These findings on cART-altered EV content can also be applied to general viral inhibitors (interferons) which are used to treat other chronic infections. Additionally, we describe unique mechanisms of ESCRT pathway manipulation by antivirals, specifically the targeting of VPS4. Collectively, these data imply that, despite antiretroviral therapy, EVs containing viral products are continually released and may cause neurocognitive and immunological dysfunction.

The potential role of gender in the occurrence of HIV-related neurocognitive impairment (NCI) and associations with markers of HIV-related immune activity has not been previously examined. In this study 149 antiretroviral-naïve seropositive subjects in Nigeria (SP, 92 women and 57 men) and 58 seronegative (SN, 38 women and 20 men) were administered neuropsychological testing that assessed 7 ability domains. From the neuropsychological test scores was calculated a global deficit score (GDS), a measure of overall NCI. Percentages of circulating monocytes and plasma HIV RNA, soluble CD163 and soluble CD14 levels were also assessed. HIV SP women were found to be younger, more educated and had higher CD4+ T cell counts and borderline higher viral load measures than SP men. On the neuropsychological testing, SP women were more impaired in speed of information processing and verbal fluency and had a higher mean GDS than SN women. Compared to SP men, SP women were also more impaired in speed of information processing and verbal fluency as well as on tests of learning and memory. Numbers of circulating monocytes and plasma sCD14 and sCD163 levels were significantly higher for all SP versus all SN individuals and were also higher for SP women and for SP men versus their SN counterparts. Among SP women, soluble CD14 levels were slightly higher than for SP men, and SP women had higher viral load measurements and were more likely to have detectable virus than SP men. Higher sCD14 levels among SP women correlated with more severe global impairment, and higher viral load measurements correlated with higher monocyte numbers and sCD14 and sCD14 levels, associations that were not observed for SP men. These studies suggest that the risk of developing NCI differ for HIV infected women and men in Nigeria and, for women, may be linked to effects from higher plasma levels of HIV driving activation of circulating monocytes.

Background: HIV-exposed but uninfected (HEU) children may be at an increased risk of impaired growth when compared with their HIV-unexposed and uninfected (HUU) counterparts. We compared the growth patterns of HEU to HUU children in Nigeria. Methods: Pregnant women with and without HIV infection were enrolled at the Plateau State Specialist Hospital, Jos, Nigeria. Infants born to these mothers were recruited at birth and the mother–infant pairs followed up for 18 months. Weight, length and head circumference of the infants were measured at each visit. Age- and sex-standardized Z scores were generated for each anthropometric measure using the World Health Organization Child Growth Standards. Children with length-for-age, weight-for-age and weight-for-length Z scores <−2 were classified as stunted, underweight and wasted, respectively. Results: Of 415 children (307 HEU and 108 HUU) recruited for this study, 117 (28.4%), 9 (2.2%) and 32 (7.8%) infants were stunted, underweight and wasted, respectively, at birth. In a multivariable longitudinal analysis, the odds of stunting were higher among HEU as compared with HUU children [adjusted odds ratio: 2.4 (95% confidence interval: 1.4–4.1)]. Similarly, odds of being underweight were higher among the HEU children [adjusted odds ratio: 1.6 (95% confidence interval: 1.1–2.2)]. Conclusions: Linear and ponderal growth were more impaired among HEU as compared with HUU children in Nigeria during the first 18 months of life. Further studies are needed to explore the causal basis for these differences.

Annual fasting during the month of Ramadan is observed in Muslim countries, some of which have widespread HIV infection. We studied treatment adherence and customary practices among 142 fasting 'FT' and 101 non-fasting 'NFT' patients on anti-retroviral therapy (ART) in Nigeria. Adherence on ART among FT and NFT patients was similar during Ramadan, 96% and 98%, and ever since commencement of ART, 80% and 88%, respectively. FT patients altered their typical daily behaviors by advancing morning and delaying evening doses thereby prolonging dosing intervals, eating heavier meals pre-dawn and on breakfast at sunset (78%), and changing or reducing their sleeping and waking times (40%). This preliminary study suggests that adherence and drug taking frequency appear uncompromised in FT HIV infected patients on ARVs.

High levels of viral suppression and low prevalence of drug resistance mutations (DRMs) were seen in this cohort participating in an ART adherence study in Northern Nigeria. Self-reported good adherence and optimal Rx refill rates were reported as significant predictors of VL suppression. Our findings indicate that ART adherence will improve significantly regardless of whether HIV-infected adults received peer-education-based medication adherence interventions or standard of care services.

Mononuclear cells play key roles in the pathogenic mechanisms leading to HIV associated neurocognitive disorders (HAND). We examined the association between HIV DNA within peripheral blood mononuclear cell (PBMC) subsets and HAND in Nigeria. PBMCs were collected at baseline from 36 antiretroviral naïve participants. CD14+ cells and T&B lymphocyte fractions were isolated by, respectively, positive and negative magnetic bead separation. Total HIV DNA within CD14+ and T&B cells were separately quantified using real-time PCR assay targeting HIV LTR-gag and cell input numbers determined by CCR5 copies/sample. Utilizing demographically adjusted T scores obtained from a 7-domain neuropsychological test battery, cognitive status was determined by the global deficit score (GDS) approach, with a GDS of ≥0.5 indicating cognitive impairment. In a linear regression adjusting for plasma HIV RNA, CD4 and lymphocyte count, Beck’s depression score, and years of education, there was 0.04 lower log10 HIV DNA copies within T&B lymphocytes per unit increase in global T score (p= 0.02). Adjusting for the same variables in a logistic regression, the odds of cognitive impairment were 6.2 times greater per log10 increase in HIV DNA within T&B lymphocytes (p= 0.048). The association between cognitive impairment and HIV DNA within CD14+ monocytes did not reach statistical significance. In this pretreatment cohort with mild cognitive dysfunction we found a strong association between levels of HIV DNA within the lymphocyte subset and HAND independent of plasma HIV RNA. These findings likely reflect the neurologic impact of a larger HIV reservoir and active viral replication.

was found to be more common in situations where a child's HIV status was only known to the primary caregiver [7]. The findings of this study, however, were questioned because children on syrups and suspensions were excluded. Another study found similar levels of self-reported adherence in children receiving ART in Kampala, Uganda, which were comparable to the reported levels in resource-rich settings [8]. In addition, the study found that financial constraints in purchasing ARV medications were a major barrier to adherence. An earlier report also found financial constraints to be the most common reason for non-adherence among children on ART in Nigeria [9]. However, this study had a sample size of 40 children and it would be difficult to draw comparative conclusions given the small sample size. While studies of African adults showed that good adherence to ART is possible despite poor social circumstances [10-12], there are limited data on ART adherence among African children, and hence the need for the current study. To address this, our study determined the rates and factors associated

Background Access to antiretroviral therapy (ART) during pregnancy and breastfeeding for mothers with HIV has resulted in fewer children acquiring HIV peri- and postnatally, resulting in an increase in the number of children who are exposed to the virus but are not infected (HEU). HEU infants have an increased likelihood of childhood infections and adverse growth outcomes, as well as increased mortality compared to their HIV-unexposed (HUU) peers. We explored potential differences in the gut microbiota in a cohort of 272 Nigerian infants born to HIV-positive and negative mothers in this study during the first 18 months of life. Results The taxonomic composition of the maternal vaginal and gut microbiota showed no significant differences based on HIV status, and the composition of the infant gut microbiota at birth was similar between HUU and HEU. Longitudinal taxonomic composition of the infant gut microbiota and weight-for-age z-scores (WAZ) differed depending on access to breast milk. HEU infants displayed overall lower WAZ than HUU infants at all time points. We observed a significantly lower relative abundance of Bifidobacterium in HEU infants at 6 months postpartum. Breast milk composition also differed by time point and HIV infection status. The antiretroviral therapy drugs, lamivudine and nevirapine, as well as kynurenine, were significantly more abundant in the breast milk of mothers with HIV. Levels of tiglyl carnitine (C5) were significantly lower in the breast milk of mothers without HIV. ART drugs in the breast milk of mothers with HIV were associated with a lower relative abundance of Bifidobacterium longum. Conclusions Maternal HIV infection was associated with adverse growth outcomes of HEU infants in this study, and these differences persist from birth through at least 18 months, which is a critical window for the development of the immune and central nervous systems. We observed that the relative abundance of Bifidobacterium spp. was significantly lower in the gut microbiota of all HEU infants over the first 6 months postpartum, even if HEU infants were receiving breast milk. Breastfeeding was of benefit in our HEU infant cohort in the first weeks postpartum; however, ART drug metabolites in breast milk were associated with a lower abundance of Bifidobacterium.