After Antiretroviral Treatment Research Articles

Time to incident hypertension and independent predictors among people living with HIV in Nigeria.

Understanding the time to hypertension occurrence after antiretroviral treatment (ART) initiation in people living with HIV (PLHIV) and its determinants is important for designing interventions for control. This study sought to estimate the median time of ART use to hypertension onset and its predictors in Nigerian PLHIV. A retrospective longitudinal study. This retrospective review of 2503 normotensive adult PLHIV (⩾18 years) from 2004 to 2020 in two HIV clinics in Nigeria. Incident hypertension was based on clinical diagnosis or two consecutive blood pressure readings ⩾140/90 mmHg, taken during the 8 months of data collection. Survival event was defined as incident hypertension during follow-up or interview day for observed patients unless they were right censored. The Kaplan-Meier survival curve was used to estimate the survival probabilities of hypertension. The Cox proportional hazard model was fitted to identify predictors of hypertension at p < 0.05. A total of 2503 PLHIV was followed up. The majority were females (74.6%) and on Dolutegravir-based therapy (93.0%). About 22 (0.9%) were diabetic. Median age at ART initiation was 35 (interquartile range: 29-41) years. The median period of follow-up was 12.0 ± 3.9 years. The cumulative incidence of hypertension was 32.5% (381/2540), with an incidence rate of 40.1/1000 person-years. The median time to incident hypertension was 17.0 years (95% CI: 12.5-21.5 years). Shorter hypertension-free survival times were seen in males, those aged 60+, with diabetes, unsuppressed viral load, history of tuberculosis, other opportunistic infections, or co-trimoxazole use. Significant risk factors included male sex (adjusted odds ratio (AOR) = 1.3, 95% CI = 1.1-1.6), middle age (AOR = 2.3, 95% CI = 1.7-3.2), old age (AOR = 5.6, 95% CI = 3.9-8.4), and unsuppressed viral load (AOR = 1.9, 95% CI = 1.3-2.7). Hypertension is commoner among PLHIV with unsuppressed viral load, males, and persons older than 40 years. Effective ART with viral suppression remains essential. Incorporating regular hypertension screening and treatment into HIV care is necessary for optimum health outcomes.

The effect of HIV treatment interruption on subsequent immunologic response.

CD4 count recovery after antiretroviral treatment (ART) initiation has been thoroughly examined in HIV infection. However, immunologic response after ART restart following care interruption is less well studied. We compare the CD4 trends before disengagement from care and after ART re-initiation. Data were obtained from the East-Africa International epidemiology Databases to Evaluate AIDS (IeDEA) Collaboration (N= 62,534). CD4 trends before disengagement, during disengagement, and after ART re-initiation were simultaneously estimated through a linear mixed model with two subject-specific knots placed at the time of disengagement and treatment re-initiation. We also estimated CD4 trends conditional on the baseline CD4 value. 10,961 patients returned to care after disengagement from care, with the median (IQR) time of gap in care being 2.7 (2.1, 5.4) months. Our model showed that CD4 increases after ART re-initiation were much slower than those before disengagement. Assuming that disengagement from care occurs 12 months after ART initiation and a three-month treatment gap, CD4 counts at 3 years since ART initiation would be lower by 36.5 cells/$\mu L$ than those obtained under no disengagement. Given that poorer CD4 restoration is associated with increased mortality/morbidity, specific interventions targeting at better retention to care are urgently required.

Correlation between CD4/CD8 ratio and neurocognitive performance during early HIV infection.

CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART). This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART-naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury. In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p < 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002-0.29; p=0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p=0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p=0.04). The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection.

Burden of sexually transmitted infections from acute HIV infection among women in South Africa: Evidence from a prospective cohort study

PurposeHIV and other sexually transmitted infections (STIs) often co-occur. However, less evidence exists on the long-term STI dynamics among persons living with HIV in sub-Saharan Africa to inform interventions. We investigated the incidence, prevalence and factors associated with STIs, starting from acute HIV infection in a cohort of South African women. MethodsThe CAPRISA002 study enrolled women with acute HIV infection and performed STI testing and treatment 1-2 times annually from 2004-2020. We estimated STI incidence, re-infection, and prevalence trends before and after antiretroviral treatment (ART). We fitted Cox regression models to identify factors associated with STIs. ResultsWe followed up 235 women (median age = 25 years, IQR 22-29) for 7.5 years (IQR 5.7-10.8). New STI and re-infection cases per 100 person-years (PYs) were 5.1 and 9.5 for Neisseria gonorrhoeae (NG), 7.4 and 14.7 for Chlamydia trachomatis (CT), 8.0 and 26.6 for Trichomonas vaginalis (TV), 7.7 and 16.7 for Mycoplasma genitalium (MG) and 25.2 and 37.3 for any STI. STI incidence, was associated with HIV log10 viral load (AHR = 1.24, 95% CI 1.06-1.44), active syphilis (AHR = 16.55, 95% CI 7.49-36.55), a positive HSV-2 PCR (AHR = 1.54, 95% CI 1.01-2.35), bacterial vaginosis (AHR = 1.48, 95% CI 1.01-2.18), recent regular sexual partners at enrolment (one vs none: AHR = 2.62, 95% CI 1.41-4.87; two plus vs none: AHR = 3.68, 95% CI 1.79-7.59) and age (5-year fold: AHR = 0.80, 95% CI 0.70-0.92). ConclusionThe persistent STI/HIV co-infection burden among South African women highlights that early HIV diagnosis and ART initiation needs to be combined with better STI care for women and their partners to prevent HIV and STI transmission.

Determinants of long-term survival in late HIV presenters: The prospective PISCIS cohort study.

SummaryBackgroundLate HIV diagnosis (i.e CD4≤350 cells/µL) is associated with poorer outcomes. However, determinants of long-term mortality and factors influencing immune recovery within the first years after antiretroviral treatment (ART) initiation are poorly defined.MethodsFrom PISCIS cohort, we included all HIV-positive adults, two-year survivors after initiating ART between 2005–2019. The primary outcome was all-cause mortality according to the two-year CD4 count. We used Poisson regression. The secondary outcome was incomplete immune recovery (i.e., two-year CD4<500 cells/µL). We used logistic regression and propensity score matching.FindingsWe included 2,719 participants (16593·1 person-years): 1441 (53%) late presenters (LP) and 1278 non-LP (1145 non-LP with two-year CD4 count >500 cells/µL, reference population). Overall, 113 patients (4·2%) died. Mortality was higher among LP with two-year CD4 count 200–500 cells/µL (aMRR 1·95[95%CI:1·06-3·61]) or <200 cells/µL (aMRR 4·59[2·25-9·37]).Conversely, no differences were observed in participants with two-year CD4 counts >500 cells/µL, regardless of being initially LP or non-LP (aMRR 1·05[0·50-2·21]). Mortality rates within each two-year CD4 strata were not affected by the initial CD4 count at ART initiation (test-interaction, p = 0·48). The stronger factor influencing immune recovery was the CD4 count at ART initiation. First-line integrase-inhibitor-(INSTI)-based regimens were associated with reduced mortality compared to other regimens (aMRR 0·54[0·31-0·93]) and reduced risk of incomplete immune recovery in LP (aOR 0·70[0·52-0·95]).InterpretationTwo-year immune recovery is a good early predictor of long-term mortality in LP after surviving the first high-risk 2 years. Nearly half experienced a favorable immune recovery with a life expectancy similar to non-LP. INSTI-based regimens were associated with higher rates of successful immune recovery and better survival compared to non-INSTI regimens.FundingSouthern-Denmark University, Danish AIDS-foundation, and Region of Southern Denmark.

Low frequency of cytomegalovirus (CMV) disease despite high prevalence of CMV viraemia in patients with advanced HIV infection: a clinical and immunological 48-week follow-up study.

The aim of the study was to investigate the dynamics of cytomegalovirus (CMV) replication and CMV-specific immune response recovery after antiretroviral treatment (ART) initiation in patients with advanced HIV infection. A prospective observational study of patients with HIV infection and CD4 counts of <100 cells/µL was carried out (September 2015 to July 2018). HIV viral load (VL), CD4 count and CMV VL were determined by quantitative polymerase chain reaction (PCR) at baseline and at 4, 12, 24 and 48weeks, and CMV-specific immune response was determined by QuantiFERON-CMV assay at baseline and 48weeks. All patients were started on ART but only those with CMV end-organ disease (EOD) received anti-CMV treatment. Fifty-three patients with a median age of 43.6 [interquartile range (IQR) 36.7-52.4] years were included in the study. At baseline, the median CD4 count was 30 cells/µL (IQR 20-60 cells/µL) and the median HIV VL was 462000 HIV-1 RNA copies/mL (IQR 186000-1300000 copies/mL). At baseline, 32% patients had detectable CMV viraemia but none had detectable CMV viraemia at 48weeks. Only one of 53 (1.9%) patients developed EOD during follow-up. Seven (13.2%) patients were lost to follow-up and six (11.3%) died; none of the deaths was related to CMV. Similar percentages of patients had a CMV-specific immune response at baseline (71.7%) and at 48 weeks (70.0%). The magnitude of this response tended to increase over time [median 1.63 (IQR 0.15-5.77) IU/mL at baseline vs. median 2.5 (IQR 0.1-8.325) IU/mL at 48weeks; P=0.11]. We did not find any risk factors associated with 48-week mortality. Although the prevalence of CMV viraemia in patients with advanced HIV infection remains high, achieving a good immunological recovery through ART is enough to suppress CMV viraemia, without an increased risk of CMV EOD. The prevalence of a CMV-specific immune response was high and endured over time.

Assessment of HIV-1 integration in tissues and subsets across infection stages.

The integration of HIV DNA into the host genome contributes to lifelong infection in most individuals. Few studies have examined integration in lymphoid tissue, where HIV predominantly persists before and after antiretroviral treatment (ART). Of particular interest is whether integration site distributions differ between infection stages with paired blood and tissue comparisons. Here, we profiled HIV integration site distributions in sorted memory, tissue-resident, and/or follicular helper CD4+ T cell subsets from paired blood and lymphoid tissue samples from acute, chronic, and ART-treated individuals. We observed minor differences in the frequency of nonintronic and nondistal intergenic sites, varying with tissue and residency phenotypes during ART. Genomic and epigenetic annotations were generally similar. Clonal expansion of cells marked by identical integration sites was detected, with increased detection in chronic and ART-treated individuals. However, overlap between or within CD4+ T cell subsets or tissue compartments was only observed in 8 unique sites of the 3540 sites studied. Together, these findings suggest that shared integration sites between blood and tissue may, depending on the tissue site, be the exception rather than the rule and indicate that additional studies are necessary to fully understand the heterogeneity of tissue-sequestered HIV reservoirs.

Effects of HIV-1 genotype on baseline CD4+ cell count and mortality before and after antiretroviral therapy

To assess whether human immunodeficiency virus type 1 (HIV-1) genotype influences baseline CD4+ T lymphocyte (CD4+) cell count and mortality of patients. The study was conducted from 2014 to 2019 in Guangxi, China, and included 2845 newly diagnosed HIV patients. We used a median regression model to compare CD4+ cell counts in patients newly diagnosed with different HIV-1 genotypes, and a Cox regression model to analyze the associations between HIV-1 genotypes and mortality before and after antiretroviral treatment (ART). In newly diagnosed HIV patients, the baseline CD4+ cell counts of patients with CRF01_AE were significantly lower than those of patients with CRF07_BC, CRF08_BC, and other genotypes. Compared with CRF01_AE, patients infected with CRF07_BC (hazard ratio, 0.55; 95% CI 0.36–0.85), CRF08_BC (hazard ratio, 0.67; 95% CI 0.52–0.85), or other genotypes (hazard ratio, 0.52; 95% CI 0.29–0.94) had significantly lower mortality rates before ART. There were no significant associations between different HIV-1 genotypes and mortality after ART. HIV-1 genotype significantly influences baseline CD4+ cell count and mortality before ART in newly diagnosed HIV patients. We find no significant difference in the outcome of death after ART in patients with different HIV-1 genotypes.

Natural killer cell counts in primary HIV infection predicts disease progression and immune restoration after treatment

The relationship between NK cell counts during primary infection and disease progression or immune restoration after antiretroviral treatment (ART) was explored. We followed 462 individuals with HIV infection and measured their NK, CD4+ T, CD8+ T cell counts and viral loads. Our data showed that individuals with high NK cell counts had much lower viral loads and higher CD4+ T cell counts. NK cell counts during primary infection were negatively correlated with viral set-point and viral loads at one-year-infection point, and positively correlated with CD4+ T cell counts at one-year-infection and one-year-ART point. Moreover, the NK cell counts during primary infection can predict HIV disease progression and immune restoration after ART. In conclusion, NK cell counts during primary infection represents a potential predictive biomarker to predict HIV disease prognosis in the clinic.

The Effect of Antiretroviral Therapy on IL-6, IL-1β, TNF-α, IFN-γ Levels and their Relationship with HIV-RNA and CD4+ T Cells in HIV Patients.

Serum cytokine levels over the course of HIV infection usually increase with immunosuppression and decrease after antiretroviral treatment (ART). The aim of the study is to compare cytokine levels between HIV-infected patients (HIP) and controls and investigate the relationship between CD4+T cell count, HIV-RNA levels, and cytokine levels. The study subjects comprised ART-naive HIP (n=30) with no comorbidities and age-and sex-matched healthy controls. We measured levels of IL-6, IL-1β, TNF-α, and IFN-γ in serum samples of HIP at the beginning and at month 6 of ART and in controls. The mean age of the study subjects was 38.7 ±10.3 years, with men making up 86.7% of the study subjects (n=26). IL-6, IL-1β, and TNF-α levels were significantly higher in both ART-naive (p<0.001, p=0.002, p=0.001) and ART-experienced HIP (p<0.001) than controls. The IFN-γ level was lower in both ART-naive and ART-experienced HIP compared to controls (p=0.082 and p=0.002). There was a positive correlation between the CD4+T cell count and serum concentration of IFN- γ(r=0.320, p<0.05). While the serum IFN-γ concentration showed a negative correlation with the HIVRNA level(r=-0.412, p<0.001), the serum IL-1β, IL-6, and TNF-α concentrations showed a positive correlation with the HIV-RNA level (r=0.349, p<0.001; r:0.54, p<0.001; r:0.438, p<0.00). Although serum concentrations of IL-6, IL-1β and TNF-α showed a significant decrease after ART, they were still significantly higher than the controls. IFN-γ responded differently to ART compared to the other cytokines, indicating that it may play a distinct and important role in the pathogenesis of HIV infection.

Prevalence and Outcomes of Hepatitis B Coinfection and Associated Liver Disease Among Antiretroviral Therapy-Naive Individuals in a Rural Tanzanian Human Immunodeficiency Virus Cohort.

Background. We evaluated the prevalence of chronic hepatitis B virus (HBV) infection and liver fibrosis/cirrhosis in human immunodeficiency virus (HIV)-infected individuals enrolled in a rural Tanzanian prospective cohort and assessed hepatic fibrosis progression 12-24 months after antiretroviral treatment (ART) initiation. Methods. All ART-naive HIV-infected adults ≥15-year-old enrolled in the Kilombero and Ulanga Antiretroviral Cohort who started ART between 2005 and 2015 were included. Pre-ART factors associated with significant liver fibrosis (aspartate aminotransferase-to-platelet ratio index [APRI] >1.5) and cirrhosis (APRI > 2.0) were identified using logistic regression. Results. Of 3097 individuals screened, 227 (7.3%; 95% CI, 6.4-8.2) were hepatitis B surface antigen (HBsAg) positive. Before ART initiation, 9.1% individuals had significant liver fibrosis and 5.3% had cirrhosis. Human immunodeficiency virus/HBV-coinfected individuals were more likely to have an APRI score indicating significant fibrosis (14.2% vs 8.7%, P = .03) and cirrhosis (9.2% vs 4.9%, P = .03) than HBV-uninfected patients. CD4 cell count <200 cell/μL and alcohol consumption were independently associated with pre-ART APRI score, indicating significant fibrosis and cirrhosis in multivariable analyses. Among individuals with elevated APRI measurements pre- and 12-24 months post-ART initiation, 53 of 57 (93.0%) of HIV-monoinfected and 4 of 5 (80.0%) of HIV/HBV-coinfected had a regression to APRI < 1.5. Conclusions. Hepatic fibrosis and cirrhosis were common in our cohort, especially among HIV/HBV-coinfected individuals. The APRI improved in most patients. Pre-ART HBsAg screening and early onset of tenofovir-based ART for HIV/HBV-coinfection should be prioritized in sub-Saharan Africa.

Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study

BackgroundCerebrospinal fluid (CSF) neurofilament light chain protein (NFL) is a sensitive marker of neuronal injury in a variety of neurodegenerative conditions, including the CNS dysfunction injury that is common in untreated HIV infection. However, an important limitation is the requirement for lumbar puncture. For this reason, a sensitive and reliable blood biomarker of CNS injury would represent a welcome advance in both clinical and research settings. MethodsTo explore whether plasma concentrations of NFL might be used to detect CNS injury in HIV infection, an ultrasensitive Single molecule array (Simoa) immunoassay was developed. Using a cross-sectional design, we measured NFL in paired CSF and plasma samples from 121 HIV-infected subjects divided into groups according to stage of their systemic disease, presence of overt HIV-associated dementia (HAD), and after antiretroviral treatment (ART)-induced viral suppression. HIV-negative controls were also examined. FindingsPlasma and CSF NFL concentrations were very highly correlated (r=0.89, P<0.0001). While NFL was more than 50-fold lower plasma than CSF it was within the quantifiable range of the new plasma assay in all subjects, including the HIV negatives and the HIV positives with normal CSF NFL concentrations. The pattern of NFL changes were almost identical in plasma and CSF, both exhibiting similar age-related increases in concentrations along with highest values in HAD and substantial elevations in ART-naïve neuroasymptomatic subjects with low blood CD4+ T cells. InterpretationThese results show that plasma NFL may prove a valuable tool to evaluate ongoing CNS injury in HIV infection that may be applied in the clinic and in research settings to assess the presence if active CNS injury. Because CSF NFL is also elevated in a variety of other CNS disorders, sensitive measures of plasma NFL may similarly prove useful in other settings.

Variation and significance of helper T cells and regulatory T cells in the peripheral blood before and after antiretroviral treatment of human immunodeficiency virus-1 infected patients

Objective To investigate the changes and clinical significance of helper T cells (Th)22, Th17, Th1 and regulatory T cells (Treg) in the peripheral blood before and after antiretroviral treatment (ART) of human immunodeficiency virus (HIV)-1 infected patients. Methods Forty HIV-infected patients were recruited into this study, and 30 healthy subjects were recruited as controls. Peripheral blood of the patients was collected at baseline and after 3 months of ART treatment. The frequencies of Th22, Th17, Th1 and Treg were detected by flow cytometry. Tests for homogeneity of variance and paired t test for comparison was adopted. Spearman rank test was used for correlation analysis. Results The frequencies of peripheral Th22, Th17, Th1 and Treg from HIV-infected patients before treatment were significantly decreased compared to the healthy controls ([0.59±0.47]% vs [1.65±0.56]%[t=8.544, P 0.05). However, the Th1 frequency showed no difference compared to the baseline. The frequency of Treg in the HIV infected patients was significantly increased compared with the healthy controls ([10.76±3.76]% vs [7.01±1.88]%, t=5.003, P<0.01). However, it gradually decreased along with the ART treatment ([9.22±2.56]% after 2 months; [8.57±2.36]% after 3 months), which was still higher than that of healthy controls (t=2.984, P=0.004). The ratios of Th22/Treg, Th17/Treg and Th1/Treg of the HIV-infected patients were significantly decreased in comparison with the healthy controls (0.05±0.03 vs 0.25±0.10, t=11.69, P<0.01; 0.46±0.27 vs 1.07±0.42, t=7.728, P<0.01; 1.56±0.89 vs 3.37±1.02, t=7.052, P<0.01), and those were significantly increased after 3 months of treatment (0.17±0.10[t=6.852, P<0.01], 0.81±0.46[t=4.253, P<0.01] and 2.31±1.27[t=3.030, P<0.01]). Correlation analysis showed that the ratio of Th17/Treg of the HIV-infected patients was positively correlated with the peripheral CD4+ T cell count (r=0.312 5, P=0.049 6), and negatively correlated with HIV RNA viral load (r=-0.474 7, P=0.002 0). The ratio of Th1/Treg of the HIV-infected patients was positively correlated with the peripheral CD4+ T cell count (r=0.333 5, P=0.035 5). Conclusions Th22, Th17, Th1 and Treg cells in the peripheral blood of HIV-infected patients are closely related to CD4+ T cell count. ART can partially recover immune imbalance, and help to rebuild immune function of HIV-infected patients. Key words: Acquired immunodeficiency syndrome; Antiretroviral therapy; T-Lymphocytes, regulatory; Th22; Th17; Th1

Assessing the Costs and Effects of Antiretroviral Therapy Task Shifting From Physicians to Other Health Professionals in Ethiopia

To evaluate the effects, costs, and cost-effectiveness of different degrees of antiretroviral therapy task shifting from physician to other health professionals in Ethiopia. Two-year retrospective cohort analysis on antiretroviral therapy patients coupled with cost analysis. Facilities with minimal or moderate task shifting compared with facilities with maximal task shifting. Maximal task shifting is defined as nonphysician clinicians handling both severe drug reactions and antiretroviral drug regimen changes. Secondary analysis compares health centers to hospitals. The primary effectiveness measure is the probability of a patient remaining actively on antiretroviral therapy for 2 years; the cost measure is the cost per patient per year. All facilities had some task shifting. About 89% of patients were actively on treatment 2 years after antiretroviral treatment (ART) initiation, with no statistically significant differences between facilities with maximal and minimal or moderate task shifting. It cost about $206 per patient per year for ART, with no statistically significant difference between the comparison groups. The cost-effectiveness of maximal task shifting is similar to minimal or moderate task shifting, with the same results obtained using regression to control for facility characteristics. Shifting the handling of both severe drug reactions and antiretroviral drug regimen changes from physicians to other clinical officers is not associated with a significant change in the 2-year treatment success rate or the costs of ART care. As an observational study, these results are tentative, and more research is needed in determining the optimal patterns of task shifting.

Incomplete immune recovery of naive CD4 T-cell subsets after antiretroviral treatment (ART) in HIV-1 infection

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Upregulation of BST-2/Tetherin by HIV Infection In Vivo

The interferon-inducible antiviral factor BST-2 prevents several enveloped viruses, including HIV, from escaping infected cells. The HIV protein Vpu antagonizes this host defense. Little is known about the expression of BST-2 during HIV infection in vivo and whether it can be modulated to the host's advantage. We studied the expression of BST-2 on blood cells from HIV-infected patients during the acute and chronic phases of disease as well as after antiretroviral treatment (ART). The expression of BST-2 was increased on mononuclear leukocytes, including CD4-positive T lymphocytes from HIV-positive patients, compared to that on cells of uninfected controls. The expression of BST-2 was highest during acute infection and decreased to levels similar to those of uninfected individuals after ART. Treatment of primary blood mononuclear cells in vitro with alpha interferon or with Toll-like receptor (TLR) agonists increased the expression of BST-2 to levels similar to those found during infection in vivo. The interferon-induced levels were sufficient to overcome the Vpu protein in vitro, reducing the release of wild-type HIV. These data show that BST-2 is upregulated during HIV infection, consistent with its role as an interferon-stimulated gene. The data further suggest that this upregulation is sufficient to saturate the activity of Vpu and inhibit wild-type HIV.

Evolution of Drug-Resistant Viral Populations during Interruption of Antiretroviral Therapy

Analysis of a large number of HIV-1 genomes at multiple time points after antiretroviral treatment (ART) interruption allows determination of the evolution of drug-resistant viruses and viral fitness in vivo in the absence of drug selection pressure. Using a parallel allele-specific sequencing (PASS) assay, potential primary drug-resistant mutations in five individual patients were studied by analyzing over 18,000 viral genomes. A three-phase evolution of drug-resistant viruses was observed after termination of ART. In the first phase, viruses carrying various combinations of multiple-drug-resistant (MDR) mutations predominated with each mutation persisting in relatively stable proportions while the overall number of resistant viruses gradually increased. In the second phase, viruses with linked MDR mutations rapidly became undetectable and single-drug-resistant (SDR) viruses emerged as minority populations while wild-type viruses quickly predominated. In the third phase, low-frequency SDR viruses remained detectable as long as 59 weeks after treatment interruption. Mathematical modeling showed that the loss in relative fitness increased with the number of mutations in each viral genome and that viruses with MDR mutations had lower fitness than viruses with SDR mutations. No single viral genome had seven or more drug resistance mutations, suggesting that such severely mutated viruses were too unfit to be detected or that the resistance gain offered by the seventh mutation did not outweigh its contribution to the overall fitness loss of the virus. These data provide a more comprehensive understanding of evolution and fitness of drug-resistant viruses in vivo and may lead to improved treatment strategies for ART-experienced patients.

Functional patterns of HIV-1-specific CD4 T-cell responses in children are influenced by the extent of virus suppression and exposure

Virus-specific CD4 T cells play a critical role in antiviral immunity. HIV-1-specific CD4 T cells in chronically infected adults are mostly composed of IFN-gamma-secreting cells, whereas a selective defect in IL-2-secreting CD4 T cells has been demonstrated. HIV-1-specific IL-2-secreting CD4 T cells are key components of effective immunity. To determine the function of HIV-1-specific CD4 T cells in HIV-1 vertically infected children after antiretroviral treatment (ART). Twenty-three vertically HIV-infected children treated with ART for an extended period (mean 7 years) were retrospectively studied. The function of HIV-1-specific CD4 T cells was determined by their ability to secrete IL-2 and IFN-gamma after stimulation with HIV-1 p55 gag protein using polychromatic flow cytometry. : Substantial differences in the patterns of CD4 T-cell responses were associated with different conditions of response to ART. Interestingly, children with suppression of viraemia below 50 HIV-1-RNA copies/ml of plasma for at least 2 years showed dominant IL-2 CD4 T-cell responses; children with viraemia below 50 copies but experiencing transient blips of viraemia showed polyfunctional (IL-2 plus IFN-gamma) CD4 T-cell responses; children with uncontrolled high viraemia levels had dominant IFN-gamma CD4 T-cell responses. Furthermore, the total frequency of HIV-1-specific CD4 T cells including IL-2 and IFN-gamma-secreting cells was significantly higher compared with HIV-infected adults with chronic infection. The higher frequency of HIV-1-specific CD4 T cells in children compared with adults and the recovery of IL-2-secreting CD4 T cells after successful ART-mediated suppression of virus replication indicate a greater capacity of immune restoration in children than adults.

Gender-specific aspects of the burden of HIV/AIDS in South Africa— Communicable diseases

HIV and other sexually transmitted infections (STIs) often co-occur. However, less evidence exists on the long-term STI dynamics among persons living with HIV in sub-Saharan Africa to inform interventions. We investigated the incidence, prevalence and factors associated with STIs, starting from acute HIV infection in a cohort of South African women.The CAPRISA002 study enrolled women with acute HIV infection and performed STI testing and treatment 1-2 times annually from 2004-2020. We estimated STI incidence, re-infection, and prevalence trends before and after antiretroviral treatment (ART). We fitted Cox regression models to identify factors associated with STIs.We followed up 235 women (median age = 25 years, IQR 22-29) for 7.5 years (IQR 5.7-10.8). New STI and re-infection cases per 100 person-years (PYs) were 5.1 and 9.5 for Neisseria gonorrhoeae (NG), 7.4 and 14.7 for Chlamydia trachomatis (CT), 8.0 and 26.6 for Trichomonas vaginalis (TV), 7.7 and 16.7 for Mycoplasma genitalium (MG) and 25.2 and 37.3 for any STI. STI incidence, was associated with HIV log10 viral load (AHR = 1.24, 95% CI 1.06-1.44), active syphilis (AHR = 16.55, 95% CI 7.49-36.55), a positive HSV-2 PCR (AHR = 1.54, 95% CI 1.01-2.35), bacterial vaginosis (AHR = 1.48, 95% CI 1.01-2.18), recent regular sexual partners at enrolment (one vs none: AHR = 2.62, 95% CI 1.41-4.87; two plus vs none: AHR = 3.68, 95% CI 1.79-7.59) and age (5-year fold: AHR = 0.80, 95% CI 0.70-0.92).The persistent STI/HIV co-infection burden among South African women highlights that early HIV diagnosis and ART initiation needs to be combined with better STI care for women and their partners to prevent HIV and STI transmission.

Use of interleukin 15 to enhance interferon-γ production by antigen-specific stimulated lymphocytes from rhesus macaques

The enzyme-linked immune spot (ELISPOT) assay is receiving increased attention as a means for quantifying antigen-specific CD8 T-cell responses in rhesus macaques. Further improving the sensitivity of this assay could aid in the evaluation of vaccine candidates and/or immune therapeutic candidates. Interleukin (IL)-15 has been demonstrated to stimulate expansion of human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) and to regulate homeostatic proliferation of CD8+ memory cells. We evaluated the in vitro effect of IL-15 to increase the detection of interferon-γ (IFN-γ) production by antigen-specific stimulated lymphocytes from a group of rhesus macaques exposed to simian-human immunodeficiency virus (SHIV) and a second group infected with SIVmac251, before and after antiretroviral treatment (ART). Results from these studies demonstrate that the presence of IL-15 during stimulation in a peptide-based ELISPOT assay greatly enhanced IFN-γ production in both SHIV and simian immunodeficiency virus (SIV)-infected macaques. IFN-γ production was mainly mediated by CD8 lymphocytes. The optimal concentrations of IL-15 that give enhancement of IFN-γ production to specific antigen, without a significant increase in the spontaneous IFN-γ release, ranged from 0.5 to 2.5 ng/ml. The mean number of IFN-γ spots was increased 3.1- to 3.6-fold in response to SIV gag or HIV env peptide pools, respectively, in peripheral blood mononuclear cells (PBMC) from SHIV-infected macaques. Similarly, in SIV-infected macaques, IL-15 increased the mean number of IFN-γ spots 2.7-fold in response to both SIV gag and env peptide pools. In samples obtained after ART in the same macaques, the increase factor was 2.5 for SIV gag and 1.8 for the env peptide pools. Thus, the sensitivity of the ELISPOT assay can be enhanced by addition of IL-15. This modified assay will be useful for detection of low frequencies of IFN-γ producing cells in rhesus macaques.