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International audience; Background: Global HIV-1 genetic diversity and evolution form a major challenge to treatment and prevention efforts. An increasing number of distinct HIV-1 recombinants have been identified worldwide, but their contribution to the global epidemic is unknown. We aimed to estimate the global and regional distribution of HIV-1 recombinant forms during 1990-2015.Methods: We assembled a global HIV-1 molecular epidemiology database through a systematic literature review and a global survey. We searched the PubMed, Embase (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) databases for HIV-1 subtyping studies published from Jan 1, 1990, to Dec 31, 2015. Unpublished original HIV-1 subtyping data were collected through a survey among experts in the field who were members of the WHO-UNAIDS Network for HIV Isolation and Characterisation. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. Countries were grouped into 14 regions and analyses were done for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV in each country to generate regional and global estimates of numbers and proportions of HIV-1 recombinants in each time period. The systematic review is registered with PROSPERO, CRD42017067164.Findings: Our global data collection yielded an HIV-1 molecular epidemiology database of 383 519 samples from 116 countries in 1990-2015. We found that the proportion of recombinants increased over time, both globally and in most regions, reaching 22·8% (7 978 517 of 34 921 639) of global HIV-1 infections in 2010-15. Both the proportion and the number of distinct CRFs detected increased over time to 16·7% and 57 CRFs in 2010-15. The global and regional distribution of HIV-1 recombinants was diverse and evolved over time, and we found large regional variation in the numbers (0-44 CRFs), types (58 distinct CRFs), and proportions (0-80·5%) of HIV-1 recombinants. Globally, CRF02_AG was the most prevalent recombinant, accounting for 33·9% (2 701 364 of 7 978 517) of all recombinant infections in 2010-15. URFs accounted for 26·7% (2 131 450 of 7 978 517), CRF01_AE for 23·0% (1 838 433), and other CRFs for 16·4% (1 307 270) of all recombinant infections in 2010-15. Although other CRFs accounted for small proportions of infections globally (

Objective: Assess adverse perinatal outcomes associated with antenatal antiretroviral therapy (ART) regimens. Design: Systematic review and network meta-analysis of randomized controlled trials (RCTS). Methods: We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, EMBASE, and the Cochrane Central Register of Controlled Trials and four clinical trial databases from 1 January 1980 to 28 April 2018. We included RCTs of antenatal ART regimens in HIV-positive pregnant women, which assessed preterm birth (PTB), spontaneous preterm birth (sPTB), very preterm birth (VPTB), low birthweight (LBW), very low birthweight (VLBW), small-for-gestational-age (SGA), neonatal death (NND), and mother-to-child-transmission. We used random-effects network meta-analysis models to calculate relative risks for treatment comparisons and the hierarchy of treatments. Results: Of 83 260 citations identified, 10 manuscripts were included, assessing 6285 women. Compared with zidovudine (ZDV) monotherapy, we found a higher risk of LBW after exposure to zidovudine/lamivudine/efavirenz (ZDV/3TC/EFV; relative risk 1.61; 95% CI 1.03–2.51), tenofovir disoproxil fumarate/emtricitabine/ritonavir-boosted lopinavir (TDF/FTC/LPV/r; 1.64; 1.18–2.29), or zidovudine/lamivudine/ritonavir-boosted lopinavir (ZDV/3TC/LPV/r; 1.87; 1.58–2.20). TDF/FTC/LPV/r carried an increased risk of VLBW, compared with ZDV monotherapy (5.40; 1.08–27.08). ZDV/3TC/LPV/r posed a higher risk of PTB than ZDV monotherapy (1.43; 1.08–1.91) and a higher risk of sPTB than zidovudine/lamivudine/abacavir (ZDV/3TC/ABC) (1.81; 1.21–2.71). LPV/r-containing regimens also carried the highest risks of VPTB, SGA and NND, although the limited data showed no significant differences. Conclusion: Of the ART regimens assessed in RCTs in pregnancy, LPV/r-containing regimens were associated with the highest risks of adverse perinatal outcomes.

Background The global rise in cesarean sections has led to increasing numbers of pregnant women with a history of previous cesarean section. Policy in many high-income settings supports offering these women a choice between planned elective repeat cesarean section (ERCS) or planned vaginal birth after previous cesarean (VBAC), in the absence of contraindications to VBAC. Despite the potential for this choice to affect women’s subsequent risk of experiencing pelvic floor disorders, evidence on the associated effects to fully counsel women is lacking. This study investigated the association between planned mode of birth after previous cesarean section and the woman’s subsequent risk of undergoing pelvic floor surgery. Methods and findings A population-based cohort study of 47,414 singleton term births in Scotland between 1983 to 1996 to women with 1 or more previous cesarean sections was conducted using linked Scottish national routine datasets. Cox regression was used to investigate the association between planned as well as actual mode of birth and women’s subsequent risk of having any pelvic floor surgery and specific types of pelvic floor surgery adjusted for sociodemographic, maternal medical, and obstetric-related factors. Over a median of 22.1 years of follow-up, 1,159 (2.44%) of the study population had pelvic floor surgery. The crude incidence rate of any pelvic floor surgery per 1,000 person-years was 1.35, 95% confidence interval (CI) 1.27 to 1.43 in the overall study population, 1.75, 95% CI 1.64 to 1.86 in the planned VBAC group and 0.66, 95% CI 0.57 to 0.75 in the ERCS group. Planned VBAC compared to ERCS was associated with a greater than 2-fold increased risk of the woman undergoing any pelvic floor surgery (adjusted hazard ratio [aHR] 2.38, 95% CI 2.03 to 2.80, p < 0.001) and a 2- to 3-fold increased risk of the woman having surgery for pelvic organ prolapse or urinary incontinence (aHR 3.17, 95% CI 2.47 to 4.09, p < 0.001 and aHR 2.26, 95% CI 1.79 to 2.84, p < 0.001, respectively). Analysis by actual mode of birth showed these increased risks were only apparent in the women who actually had a VBAC, with the women who needed an in-labor non-elective repeat cesarean section having a comparable risk of pelvic floor surgery to those who had an ERCS. The main limitation of this study is the potential for misclassification bias. Conclusions This study suggests that among women with previous cesarean section giving birth to a singleton at term, planned VBAC compared to ERCS is associated with an increased risk of the woman subsequently undergoing pelvic floor surgery including surgery for pelvic organ prolapse and urinary incontinence. However, these risks appear to be only apparent in women who actually give birth vaginally as planned, highlighting the role of vaginal birth rather than labor in pelvic floor dysfunction requiring surgery. The findings provide useful additional information to counsel women with previous cesarean section about the risks and benefits associated with their future birth choices.

Background The World Health Organisation (WHO) recommends immediate initiation of lifelong antiretroviral therapy (ART) for all people living with HIV, including pregnant women. As a result, an increasing number of women living with HIV (WLHIV) conceive while taking ART, the vast majority of whom reside in low- and middle-income countries (LMICs). We aimed to assess the association between timing of ART initiation and perinatal outcomes. Methods We conducted a systematic literature review by searching PubMed, CINAHL (Ebscohost), Global Health (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials and four clinical trial databases (WHO International Clinical Trials Registry Platform, the Pan African Clinical Trials Registry, the ClinicalTrials.gov database, and the ISRCTN Registry) from Jan 1, 1980 to April 28, 2018. We identified studies reporting specific perinatal outcomes among pregnant WLHIV according to timing of ART initiation and extracted data. Perinatal outcomes assessed were preterm birth ( Results Of 51,874 unique citations, 25 studies (8 prospective and 17 retrospective cohort studies) were eligible for analysis, including 40,920 WLHIV. Preconception ART initiation was associated with a significantly increased risk of preterm birth (relative risk 1.16, 95% CI 1.03-1.31), compared to antenatal ART initiation. Preconception ART initiation was not significantly associated with very preterm birth, low birthweight, very low birthweight, small for gestational age, very small for gestational age, or neonatal death. First trimester exposure (i.e. preconception or first trimester initiation) was not significantly associated with any increased risk of adverse perinatal outcomes. No significant association between timing of ART initiation and adverse perinatal outcomes was found in the studies of higher quality and those conducted in LMICs. Conclusion Preconception ART initiation is associated with preterm delivery, but no other perinatal outcomes. In LMICs, where most pregnant WLHIV reside, the timing of ART initiation was not associated with any adverse perinatal outcomes.

Assess adverse perinatal outcomes in pregnant women living with HIV (WLHIV) receiving HAART or zidovudine (ZDV) monotherapy, compared with antiretroviral therapy (ART)-naive WLHIV and HIV-negative women.Systematic review and meta-analysis.We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between 1 January 1980 and 20 April 2020. We included studies reporting on the association of pregnant WLHIV receiving HAART or ZDV monotherapy with 11 perinatal outcomes: preterm birth (PTB), very PTB, spontaneous PTB (sPTB), low birth weight (LBW), very LBW, term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Random-effects meta-analyses were conducted.Sixty-one cohort studies assessing 409 781 pregnant women were included. WLHIV receiving ZDV monotherapy were associated with a decreased risk of PTB [relative risk 0.70, 95% confidence interval (CI) 0.62-0.79] and LBW (0.77, 0.67-0.88), and comparable risk of SGA, compared with ART-naive WLHIV. WLHIV receiving ZDV monotherapy had a comparable risk of PTB and LBW, and an increased risk of SGA (1.16, 1.04-1.30) compared with HIV-negative women. In contrast, WLHIV receiving HAART were associated with a comparable risk of PTB and LBW, and increased risk of SGA (1.38, 1.09-1.75), compared with ART-naive WLHIV. WLHIV receiving HAART were associated with an increased risk of PTB (1.55, 1.38-1.74), sPTB (2.09, 1.48-2.96), LBW (1.79, 1.51-2.13), term LBW (1.88, 1.23-2.85), SGA (1.80,1.34-2.40), and VSGA (1.22, 1.10-1.34) compared with HIV-negative women.Pregnant WLHIV receiving HAART have an increased risk of a wide range of perinatal outcomes compared with HIV-negative women.

Maternal HIV infection is associated with adverse pregnancy outcomes, but the mechanisms remain unknown. The course of pregnancy is regulated by immunological processes and HIV infection and antiretroviral therapy (ART) impact key immune mechanisms, which may disrupt the immune programme of pregnancy. We evaluated a broad range of systemic cytokines at each trimester of pregnancy in 56 women living with HIV (WLHIV) and 68 HIV-negative women, who were enrolled in a prospective pregnancy cohort study in Soweto, South Africa. The pro-inflammatory cytokine IP-10 was detected in each trimester in all WLHIV, which was significantly more than in HIV-negative women. The anti-viral cytokine IFNλ1 was detected more frequently in WLHIV, whereas IFNβ and IFNλ2/3 were detected more frequently in HIV-negative women. Th1 cytokines IL-12 and IL-12p70, Th2 cytokine IL-5, and Th17 cytokine IL-17A were detected more frequently in WLHIV throughout pregnancy. Il-6, IL-9, and IL-10 were more commonly detected in WLHIV in the first trimester. Trends of increased detection of Th1 (IL-2, IL-12p70), Th2 (IL-4, Il-5, Il-13) and Th17 (IL-17A, Il-17F, IL-21, IL-22) cytokines were associated with small-for-gestational-age babies. Our findings indicate that maternal HIV/ART is associated with distinct systemic cytokine profiles throughout pregnancy.

Global HIV-1 genetic diversity forms a major obstacle to the development of an HIV vaccine. It may be necessary to employ subtype-specific HIV-1 vaccines in individual countries according to their HIV-1 subtype distribution. We estimated the global and regional need for subtype-specific HIV-1 vaccines. We took into account the proportions of different HIV-1 variants circulating in each country, the genetic composition of HIV-1 recombinants, and the different genome segments (gag, pol, env) that may be incorporated into vaccines. We modeled different scenarios according to whether countries would employ subtype-specific HIV-1 vaccines against (1) the most common subtype; (2) subtypes contributing more than 5% of HIV infections; or (3) all circulating subtypes. For therapeutic vaccines targeting the most common HIV-1 subtype in each country, 16.5 million doses of subtype C vaccine were estimated globally, followed by subtypes A (14.3 million) and B (4.2 million). A vaccine based on env required 2.6 million subtype E doses, and a vaccine based on pol required 4.8 million subtype G doses. For prophylactic vaccines targeting the most common HIV-1 subtype in each country, 1.9 billion doses of subtype A vaccine were estimated globally, followed by subtype C (1.1 billion) and subtype B (1.0 billion). A vaccine based on env required 1.2 billion subtype E doses, and a vaccine based on pol required 0.3 billion subtype G doses. If subtype-specific HIV-1 vaccines are also directed against less common subtypes in each country, vaccines targeting subtypes D, F, H, and K are also needed and would require up to five times more vaccine doses in total. We conclude that to provide global coverage, subtype-specific HIV-1 vaccines need to be directed against subtypes A, B, and C. Vaccines targeting env also need to include subtype E and those targeting pol need to include subtype G.

Background Preterm birth is the leading cause of neonatal and child mortality worldwide. Maternal HIV infection and antiretroviral treatment (ART) increase the rate of preterm birth, but the underlying mechanisms remain unknown, limiting progress in prediction, prevention and treatment. While overall γδ T cell levels remain constant, acute HIV infection is associated with a depletion of the Vδ2 subset and an increase in the Vδ1 subset, which do not return to baseline with ART. γδ T cells have also been implicated in adverse pregnancy outcomes and we therefore investigated the potential association between maternal HIV infection, peripheral γδ T cell frequencies and preterm birth. Methods Study participants were HIV positive (n = 47) and HIV negative (n = 45) women enrolled in a prospective pregnancy cohort study at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Women were enrolled in early pregnancy and gestational age was accurately determined by first trimester ultrasound scan. Peripheral blood samples were collected in each trimester and peripheral blood mononuclear cells isolated. Frequencies of γδ T cells, Vδ1+ and Vδ2+ γδ T cell subsets, and CCR6 chemokine receptor expression were determined by flow cytometry. Results Total γδ T cell levels were similar between HIV positive and HIV negative women throughout pregnancy. However, in each trimester maternal HIV infection was associated with reduced levels of the Vδ2+ subset and increased levels of the Vδ1+ subset, leading to a reversal of the Vδ1/Vδ2 ratio. Timing of ART initiation among HIV positive women did not affect levels of γδ T cells, the Vδ1+ and Vδ2+ subsets, or the Vδ1/Vδ2 ratio. Importantly, preterm birth was associated with lower total γδ T cell levels in early pregnancy and γδ T cell frequencies were lowest in HIV positive women who delivered preterm. Moreover, in the first trimester the proportion of Vδ1+ T cells that were CCR6+ was significantly reduced in HIV+ women and women who delivered preterm, resulting in the lowest proportion of CCR6+ Vδ1 T cells in HIV positive women who delivered preterm. Conclusions Our findings suggest that altered γδ T cell frequencies may link maternal HIV infection and preterm birth. γδ T cell frequencies in early pregnancy may serve as predictive biomarkers to identify women at risk of delivering preterm.

Preterm birth is the leading cause of neonatal and child mortality worldwide. Globally, 1.4 million pregnant women are estimated to be living with HIV/AIDS, the majority of whom live in sub-Saharan Africa. Maternal HIV infection and antiretroviral treatment (ART) have been associated with increased rates of preterm birth, but the underlying mechanisms remain unknown. Acute HIV infection is associated with a rapid depletion of all three subsets of innate lymphoid cells (ILCs), ILC1s, ILC2s and ILC3s, which is not reversed by ART. ILCs have been found at the maternal–fetal interface and we therefore investigated the potential association between maternal HIV infection, peripheral ILC frequencies and preterm birth. In our study of pregnant South African women with accurately dated pregnancies, we show that maternal HIV infection is associated with reduced levels of all three ILC subsets. Preterm birth was also associated with lower levels of all three ILC subsets in early pregnancy. ILC frequencies were lowest in HIV positive women who experienced preterm birth. Moreover, ILC levels were reduced in pregnancies resulting in spontaneous onset of preterm labour and in extreme preterm birth (

Background The World Health Organization recommends protease inhibitor (PI)-based antiretroviral therapy (ART) as second-line and third-line regimens in pregnant women living with HIV (WLHIV). US, European, and UK guidelines include PI-based ART as first-line regimens, but advise against the use of lopinavir/ritonavir (LPV/r)-based ART, citing an increased risk of preterm birth (PTB). We aimed to assess the risk of adverse perinatal outcomes in WLHIV receiving PI-ART and the comparative risks associated with different PI-ART regimens. Methods We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between Jan 1, 1980, and April 20, 2020. Two investigators independently selected studies and extracted data from studies reporting on the association of pregnant WLHIV receiving PI-ART with 11 perinatal outcomes: PTB, very PTB (VPTB), spontaneous PTB (sPTB), low birth weight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Pairwise random-effects meta-analyses examined the risk of each adverse perinatal outcome in WLHIV receiving PI-ART compared to non-PI-based ART (non-PI-ART), and comparisons of different PI-ART regimens. Quality assessments of studies were performed, subgroup and sensitivity analyses were conducted based on country income status and study quality, heterogeneity assessed, and the effect of adjustment for confounding factors assessed. The protocol is registered with PROSPERO, CRD42021248987. Findings Of 94,594 studies identified, 34 cohort studies including 57,546 women met the inclusion criteria. Random-effects meta-analyses showed that PI-ART was associated with a significantly increased risk of SGA (Relative Risk [RR] 1.24, 95% CI 1.08–1.43; I2=66.7%) and VSGA (RR 1.40, 1.09–1.81; I2=0.0%), but not PTB (RR 1.09, 0.95–1.24; I2=68.3%), VPTB (RR 1.30, 0.78–2.18; I2=43.0%), sPTB (RR 1.91, 0.61–5.99; I2=95.7%), LBW (RR 1.04, 0.85–1.27; I2=63.9%), VLBW (RR 0.72, 0.37–1.43; I2=37.9%), term LBW (RR 0.94, 0.30–3.02; I2=0.0%), stillbirth (RR 1.04, 0.60–1.79; I2=0.0%), and neonatal death (RR 1.82, 0.97–3.40; I2=0.0%), compared to non-PI-ART. We found no significant differences in perinatal outcomes between ART regimens containing LPV/r, atazanavir/ritonavir (ATV/r), and darunavir/ritonavir (DRV/r), which are the most commonly used PIs. Interpretation PI-ART is associated with an increased risk of SGA and VSGA, but not PTB or other perinatal outcomes. No significant differences in perinatal outcomes were found between LPV/r, ATV/r, and DRV/r. These findings should inform clinical guidelines, and further efforts should be made to improve perinatal outcomes among pregnant WLHIV. Funding None.

Problem:Human immunodeficiency virus (HIV) infection is associated with an increased risk of adverse pregnancy outcomes, including preterm birth (PTB), despite viral suppression with antiretroviral therapy. Mucosal‐associated invariant T (MAIT) cells are an immune cell subset involved in antimicrobial immunity at mucosal surfaces. MAIT cells have been found at the maternal‐foetal interface, and MAIT cells are typically depleted early in HIV infection. We aimed to investigate changes in MAIT cells in relation to maternal HIV/ART status and PTB. Method of Study:We conducted flow cytometric analysis of peripheral blood samples from 47 HIV‐positive (HIV+) and 45 HIV‐negative (HIV−) pregnant women enrolled in a prospective pregnancy cohort study in Soweto, South Africa. Frequencies of Vα7.2+ CD161++ MAIT cells and proportions of CD4+, CD8+and double‐negative MAIT cells were compared between women with and without HIV infection, and between women with and without PTB or spontaneous preterm labour (Sp‐PTL). Results:Although overall MAIT cell frequencies were the same between HIV+ and HIV− patients, HIV+ patients had a higher proportion of CD8+MAIT cells in the first two trimesters. Women with PTB and Sp‐PTL also had a higher proportion of CD8+MAIT cells in the first trimester compared to women without these outcomes. The association between changes in MAIT cell subsets and PTB/Sp‐PTL was present in both HIV+ and HIV− women, and an additive effect on MAIT cell subsets was seen in women with both HIV infection and PTB. Conclusions:Interactions between HIV‐related and pregnancy‐related changes in MAIT cell subsets and distribution may lead to imbalances in peripheral MAIT cell subsets in early pregnancy. This may contribute to the increased risk of PTB in HIV+ patients by altering the overall functionality of the peripheral MAIT cell compartment.

Objective: To assess the association of maternal HIV infection and antiretroviral therapy (ART) with perinatal outcomes among women with accurate pregnancy dating and birth weights. Design: Prospective pregnancy cohort study in Soweto, South Africa. Methods: Gestational age was estimated by first-trimester ultrasound and birth weight was measured in a standardised manner within 24 hours of birth. The primary composite outcome “adverse perinatal outcome” included preterm birth, low birth weight, small for gestational age, stillbirth and neonatal death. Specific adverse perinatal outcomes were secondary outcomes. Logistic regression models adjusted for multiple confounders. Results: Of 633 women included in the analysis, 229 (36.2%) were HIV-positive and 404 (63.8%) HIV-negative. Among 125 HIV-positive women who provided detailed information on HIV and ART, 96.7% had clinical stage 1 of HIV disease and 98.4% were on ART during pregnancy, mostly WHO-recommended efavirenz-based ART. Among 109 HIV-positive women with information on timing of ART initiation, 38 (34.9%) initiated ART preconception and 71 (65.1%) antenatally. No newborns were HIV-positive. In univariable analysis, maternal HIV infection was associated with increased risk of the composite “adverse perinatal outcome” (OR 1.44; 95%CI 1.03, 2.03), neonatal death (OR 6.15; 95%CI 1.27, 29.88) and small for gestational age (OR 1.55; 95%CI 1.01, 2.37). After adjusting for confounders, maternal HIV infection remained associated with “adverse perinatal outcome” (adjusted OR (AOR)1.47; 95%CI 1.01, 2.14) and neonatal death (AOR 7.82; 95%CI 1.32, 46.42). No associations with timing of ART initiation were observed. Conclusion: Despite high ART coverage, good maternal health, and very low vertical HIV transmission rate, maternal HIV infection remained associated with increased risk of adverse perinatal outcomes. Larger studies using first trimester ultrasound for pregnancy dating are needed to further assess associations with specific adverse perinatal outcomes.

Background External cephalic version (ECV) reduces the chance of breech presentation at term birth and lowers the chance of a cesarean delivery. ECV services are now in place in many units in the United Kingdom but their effectiveness is unknown. The aim of this study was to investigate the reasons for breech presentation at term birth. Methods We performed a retrospective cohort study of 394 consecutive babies who were in breech presentation at term birth in a large United Kingdom maternity unit that offers ECV. The cohort was analyzed over two time periods 10 years apart: 1998–1999 and 2008–2009. Results Only 33.8 percent of women had undergone a (failed) ECV attempt. This low proportion was mainly because breech presentation was not diagnosed antenatally (27.9%). Other contributing factors were: ECV not offered by clinicians (12.2%), ECV declined by women (14%), and contraindications to ECV (10.7%). Over the 10-year period, the proportion of breech presentations that were not diagnosed antenatally increased from 23.2 to 32.5 percent (p = 0.04), which constituted 52.8 percent of women who had not undergone an ECV attempt in 2008–2009. Failure of clinicians to offer ECV reduced from 21.6 to 3.0 percent (p = 0.0001) and the proportion of women declining ECV decreased from 19.1 to 9.0 percent (p = 0.005). Overall, ECV attempts increased from 28.9 to 38.5 percent (p = 0.05). Conclusions Although ECV counseling, referral, and attempt rates have increased, failure to detect breech presentation antenatally is the principal barrier to successful ECV. Improved breech detection would have a greater impact than methods to increase ECV success rates.

A major obstacle to an HIV cure in adult infection is a viral reservoir largely composed of CTL escape mutants. Leitman et al. demonstrate that in children, but not adults, escape variant–specific CTLs are generated that can successfully “corner” the virus., Recent studies have suggested greater HIV cure potential among infected children than adults. A major obstacle to HIV eradication in adults is that the viral reservoir is largely comprised of HIV-specific cytotoxic T lymphocyte (CTL) escape variants. We here evaluate the potential for CTL in HIV-infected slow-progressor children to play an effective role in “shock-and-kill” cure strategies. Two distinct subgroups of children were identified on the basis of viral load. Unexpectedly, in both groups, as in adults, HIV-specific CTL drove the selection of escape variants across a range of epitopes within the first weeks of infection. However, in HIV-infected children, but not adults, de novo autologous variant-specific CTL responses were generated, enabling the pediatric immune system to “corner” the virus. Thus, even when escape variants are selected in early infection, the capacity in children to generate variant-specific anti-HIV CTL responses maintains the potential for CTL to contribute to effective shock-and-kill cure strategies in pediatric HIV infection.

Objective To estimate the global and regional distribution of HIV-1 subtypes and recombinants between 2000 and 2007. Design Country-specific HIV-1 molecular epidemiology data were combined with estimates of the number of HIV-infected people in each country. Method Cross-sectional HIV-1 subtyping data were collected from 65913 samples in 109 countries between 2000 and 2007. The distribution of HIV-1 subtypes in individual countries was weighted according to the number of HIV-infected people in each country to generate estimates of regional and global HIV-1 subtype distribution for the periods 2000–2003 and 2004–2007. Results Analysis of the global distribution of HIV-1 subtypes and recombinants in the two time periods indicated a broadly stable distribution of HIV-1 subtypes worldwide with a notable increase in the proportion of circulating recombinant forms (CRFs), a decrease in unique recombinant forms (URFs), and an overall increase in recombinants. In 2004–2007, subtype C accounted for nearly half (48%) of all global infections, followed by subtypes A (12%) and B (11%), CRF02_AG (8%), CRF01_AE (5%), subtype G (5%) and D(2%). Subtypes F, H, J and K together cause fewer than 1% of infections worldwide. Other CRFs and URFs are each responsible for 4% of global infections, bringing the combined total of worldwide CRFs to 16% and all recombinants (CRFs plus URFs) to 20%. Conclusions The global and regional distributions of individual subtypes and recombinants are broadly stable, although CRFs may play an increasing role in the HIV pandemic. The global diversity of HIV-1 poses a formidable challenge to HIV vaccine development. Fil: Hemelaar, Joris. University of Oxford; Reino Unido Fil: Gouwsb, Eleanor. UNAIDS; Suiza Fil: Ghysb, Peter D.. UNAIDS; Suiza Fil: Osmanov, Saladin. WHO-UNAIDS HIV Vaccine Initiative; Suiza Fil: WHO-UNAIDS Network for HIV Isolation and Characterisation. Fil: Salomon, Horacio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina

This review examines the enormous progress that has been made in the past decade in understanding the origin of HIV, HIV genetic variability, and the impact of global HIV diversity on the pandemic. Multiple zoonotic transmissions of simian immunodeficiency virus (SIV) have resulted in different HIV lineages in humans. In addition, the high mutation and recombination rates during viral replication result in a great genetic variability of HIV within individuals, as well as within populations, upon which evolutionary selection pressures act. The global HIV pandemic is examined in the context of HIV evolution, and the global diversity of HIV subtypes and recombinants is discussed in detail. Finally, the impact of HIV diversity on pathogenesis, transmission, diagnosis, treatment, the immune response, and vaccine development is reviewed.

HIV-1 genetic variability within individuals and populations plays a central role in the HIV pandemic. Multiple zoonotic transmissions of SIV to humans have resulted in distinct HIV lineages in humans which have further diversified within the population over time. High rates of mutation and recombination during HIV reverse transcription create a genetic diversity in the host which is subject to selection pressures by the immune response and antiretroviral treatment. The global distribution of HIV genetic variants and the impact of HIV diversity on pathogenesis, transmission and clinical management are reviewed. Finally, the key role of escape mutations in the immune response to HIV is discussed as well as the major challenge which HIV-1 diversity poses to HIV vaccine development. © 2012.

M Hamill and colleagues believe the UK could do more to ensure people know their HIV status

The global distribution of HIV-1 subtypes and recombinants is extremely complex and dynamic. The increasing diversity has profound implications for many aspects of the pandemic, including viral pathogenicity, transmission, diagnosis, treatment, and vaccine development. HIV-1 genetic diversity surveillance is crucial in tackling the pandemic, but systematic surveillance at national, regional, and global levels has, to date, been lacking. Here, we discuss methods for gathering representative HIV-1 molecular epidemiology data and incorporating these into a comprehensive global HIV-1 diversity monitoring system.

Objective The aim of the study was to describe pregnancies in HIV-infected teenagers. Methods A review of the case notes of HIV-infected pregnant teenagers aged 13–19 years from 12 London hospitals was carried out for the period 2000–2007. Results There were 67 pregnancies in 58 young women, of whom one was known to have acquired HIV vertically. The overall mother-to-child transmission (MTCT) rate of HIV was 1.5% (one of 66). There were 66 live births. Median ages at HIV diagnosis and conception were 17 and 18 years, respectively. Sixty-three per cent of women were diagnosed with HIV infection through routine antenatal screening. Eighty-two per cent of pregnancies (41 of 50) were unplanned, with 65% of women (26 of 40) using no contraception. Forty-three per cent of the women (20 of 46) had a past history of a sexually transmitted infection (STI). In 63 pregnancies, antiretroviral therapy was started post-conception, with prevention of HIV MTCT the only indication in 81% of cases. Fifty-eight per cent of those on highly active antiretroviral therapy (HAART) had an undetectable HIV viral load by delivery. Eighty-seven per cent were uncomplicated pregnancies. Seventy-one per cent delivered by Caesarean section and 21% (14 of 64) had a preterm delivery (

Summary Background The HIV pandemic affects 36·9 million people worldwide, of whom 1·5 million are pregnant women. 91% of HIV-positive pregnant women reside in sub-Saharan Africa, a region that also has very poor perinatal outcomes. We aimed to establish whether untreated maternal HIV infection is associated with specific perinatal outcomes. Methods We did a systematic review and meta-analysis of the scientific literature by searching PubMed, CINAHL (Ebscohost), Global Health (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials and four clinical trial databases (WHO International Clinical Trials Registry Platform, the Pan African Clinical Trials Registry, the ClinicalTrials.gov database, and the ISRCTN Registry) for studies published from Jan 1, 1980, to Dec 7, 2014. Two authors independently reviewed the studies retrieved by the scientific literature search, identified relevant studies, and extracted the data. We investigated the associations between maternal HIV infection in women naive to antiretroviral therapy and 11 perinatal outcomes: preterm birth, very preterm birth, low birthweight, very low birthweight, term low birthweight, preterm low birthweight, small for gestational age, very small for gestational age, miscarriage, stillbirth, and neonatal death. We included prospective and retrospective cohort studies and case-control studies reporting perinatal outcomes in HIV-positive women naive to antiretroviral therapy and HIV-negative controls. We used a random-effects model for the meta-analyses of specific perinatal outcomes. We did subgroup and sensitivity analyses and assessed the effect of adjustment for confounders. This systematic review and meta-analysis is registered with PROSPERO, number CRD42013005638. Findings Of 60 750 studies identified, we obtained data from 35 studies (20 prospective cohort studies, 12 retrospective cohort studies, and three case-control studies) including 53 623 women. Our meta-analyses of prospective cohort studies show that maternal HIV infection is associated with an increased risk of preterm birth (relative risk 1·50, 95% CI 1·24–1·82), low birthweight (1·62, 1·41–1·86), small for gestational age (1·31, 1·14–1·51), and stillbirth (1·67, 1·05–2·66). Retrospective cohort studies also suggest an increased risk of term low birthweight (2·62, 1·15–5·93) and preterm low birthweight (3·25, 2·12–4·99). The strongest and most consistent evidence for these associations is identified in sub-Saharan Africa. No association was identified between maternal HIV infection and very preterm birth, very small for gestational age, very low birthweight, miscarriage, or neonatal death, although few data were available for these outcomes. Correction for confounders did not affect the significance of these findings. Interpretation Maternal HIV infection in women who have not received antiretroviral therapy is associated with preterm birth, low birthweight, small for gestational age, and stillbirth, especially in sub-Saharan Africa. Research is needed to assess how antiretroviral therapy regimens affect these perinatal outcomes. Funding None.

OBJECTIVE: To estimate the global and regional distribution of HIV-1 subtypes and recombinants in 2004. DESIGN: A study was conducted in which molecular epidemiological data on HIV-1 subtype distribution in individual countries were combined with country-specific estimates of the number of people living with HIV. METHODS: HIV-1 subtype data were collected for 23 874 HIV-1 samples from 70 countries, which together accounted for 89% of all people living with HIV worldwide in 2004. The proportions of HIV-1 infections due to various subtypes detected in each country were combined with the number of HIV infected people in the respective countries to generate regional and global HIV-1 subtype distribution estimates. RESULTS: Subtype C accounted for 50% of all infections worldwide in 2004. Subtypes A, B, D and G accounted for 12%, 10%, 3% and 6%, respectively. The subtypes F, H, J and K together accounted for 0.94% of infections. The circulating recombinant forms CRF01_AE and CRF02_AG each were responsible for 5% of cases, and CRF03_AB for 0.1%. Other recombinants accounted for the remaining 8% of infections. All recombinant forms taken together were responsible for 18% of infections worldwide. CONCLUSION: Combining data on HIV-1 subtype distribution in individual countries with country-specific estimates of the number of people living with HIV provided a good method to generate estimates of the global and regional HIV-1 genetic diversity in 2004. The results could serve as an important resource for HIV scientists, public health officials and HIV vaccine developers.

The use of recombinant T cell receptors (TCRs) to target therapeutic interventions has been hindered by the naturally low affinity of TCR interactions with peptide major histocompatibility complex ligands. Here, we use multimeric forms of soluble heterodimeric alphabeta TCRs for specific detection of target cells pulsed with cognate peptide, discrimination of quantitative changes in antigen display at the cell surface, identification of virus-infected cells, inhibition of antigen-specific cytotoxic T lymphocyte activation, and identification of cross-reactive peptides. Notably, the A6 TCR specific for the immunodominant HLA A2-restricted human T cell leukemia virus type 1 Tax(11-19) epitope bound to HLA A2-HuD(87-95) (K(D) 120 microm by surface plasmon resonance), an epitope implicated as a causal antigen in the paraneoplastic neurological degenerative disorder anti-Hu syndrome. A mutant A6 TCR that exhibited dramatically increased affinity for cognate antigen (K(D) 2.5 nm) without enhanced cross-reactivity was generated; this TCR demonstrated potent biological activity even as a monomeric molecule. These data provide insights into TCR repertoire selection and delineate a framework for the selective modification of TCRs in vitro that could enable specific therapeutic intervention in vivo.

Determining the biological function of newly discovered gene products requires the development of novel functional approaches. To facilitate this task, recent developments in proteomics include small molecular probes that target proteolytic enzyme families including serine, threonine, and cysteine proteases. For the families of ubiquitin (Ub) and ubiquitin-like (UBL)-specific proteases, such tools were lacking until recently. Here, we review the advances made in the development of protein-based active site-directed probes that target proteases specific for ubiquitin and ubiquitin-like proteins. Such probes were applied successfully to discover and characterize novel Ub/UBL-specific proteases. Ub/UBL processing and deconjugation are performed by a diverse set of proteases belonging to several different enzyme families, including members of the ovarian tumor domain (OTU) protease family. A further definition of this family of enzymes will benefit from a directed chemical proteomics approach. Some of the Ub/UBL-specific proteases react with multiple Ub/UBLs and members of the same protease family can recognize multiple Ub/UBLs, underscoring the need for tools that appropriately address enzyme specificity.

OBJECTIVE: To evaluate the management and outcomes of pregnancies among women with HIV infection. Methods A retrospective cohort study was undertaken of pregnant women with HIV who delivered at one center in the UK in 2008-2012. Case notes were reviewed and detailed information extracted regarding obstetric and virological management. RESULTS: Overall, 61 pregnancies were included; 43% (26/60) were unplanned and 39% (22/57) booked late. HIV infection was diagnosed during pregnancy for 32% (19/60); 71% (12/17) were diagnosed after the first trimester. At booking, 47% of women (28/60) were not on treatment, all but one of whom commenced treatment, either for maternal reasons (CD4 count < 350 cells per mm3; 48% [13/27]) or prevention of mother-to-child-transmission (52% [14/27]). Viral load was high (> 50 copies per mL) at delivery for 13% of women (8/61). Delivery was by cesarean for 74% [45/61]. One neonate was diagnosed with HIV infection. There were 6 (10%) preterm births, 9 (15%) cases of low birth weight, 11 (18%) small-for-gestational-age neonates, and 1 (2%) stillbirth. CONCLUSION: Better pregnancy planning, earlier booking and HIV diagnosis, and optimal antiretroviral treatment should increase the proportion of women with a low viral load (< 50 copies per mL) at delivery, lead to more vaginal deliveries, and further reduce mother-to-child transmission of HIV.

OBJECTIVE/DESIGN: The global spread of HIV-1 main group (group M) has resulted in differential distributions of subtypes and recombinants, with the greatest diversity being found in sub-Saharan Africa. The explanations for the current subtype distribution patterns are likely multifactorial, but the promotion of human migrations and movements through transportation link availability and quality, summarized through 'accessibility', have been consistently cited as strong drivers. We sought to address the question of whether accessibility has been a significant factor in HIV-1 spread across mainland Africa through spatial analyses of molecular epidemiology, transport network and land cover data. METHODS: The distribution of HIV-1 subtypes and recombinants in sub-Saharan Africa for the period 1998-2008 was mapped using molecular epidemiology data at a finer level of detail than ever before. Moreover, hypotheses on the role of distance, road network structure and accessibility in explaining the patterns seen were tested using spatial datasets representing African transport infrastructure, land cover and an accessibility model of landscape travel speed. RESULTS: Coherent spatial patterns in HIV-1 subtype distributions across the continent exist, and a substantial proportion of the variance in the distribution and diversity pattern seen can be explained by variations in regional spatial accessibility. CONCLUSION: The study confirms quantitatively the influence of transport infrastructure on HIV-1 spread within Africa, presents an approach for examining potential future impacts of road development projects and, more generally, highlights the importance of accessibility in the spread of communicable diseases.

This review highlights the rising prevalence of HIV in pregnancy both in the developed and developing world. It focuses on the challenges of diagnosis and management of Pneumocystis (carinii) jiroveci pneumonia in an HIV-positive pregnant woman. Public health efforts need to continue addressing testing at the earliest opportunity, the psychosocial issues which impact negatively on the care of HIV-positive individuals and ways to reduce stigmatisation associated with this viral illness.

Modification of proteins by ubiquitin (Ub)-like proteins (UBLs) plays an important role in many cellular processes, including cell cycle progression, nuclear transport, and autophagy. Protein modification occurs via UBL-conjugating and -deconjugating enzymes, which presumably exert a regulatory function by determining the conjugation status of the substrate proteins. To target and identify UBL-modifying enzymes, we produced Nedd8, ISG15, and SUMO-1 in Escherichia coli and equipped them with a C-terminal electrophilic trap (vinyl sulfone [VS]) via an intein-based method. These C-terminally modified UBL probes reacted with purified UBL-activating (E1), -conjugating (E2), and -deconjugating enzymes in a covalent fashion. Modified UBLs were radioiodinated and incubated with cell lysates prepared from mouse cell lines and tissues to allow visualization of polypeptides reactive with individual UBL probes. The cell type- and tissue-specific labeling patterns observed for the UBL probes reflect distinct expression profiles of active enzymes, indicating tissue-specific functions of UBLs. We identify Ub C-terminal hydrolase L1 (UCH-L1) and DEN1/NEDP1/SENP8, in addition to UCH-L3, as proteases with specificity for Nedd8. The Ub-specific protease isopeptidase T/USP5 is shown to react with ISG15-VS. Furthermore, we demonstrate that the desumoylation enzyme SuPr-1 can be modified by SUMO-1-VS, a modification that is dependent on the SuPr-1 active-site cysteine. The UBL probes described here will be valuable tools for the further characterization of the enzymatic pathways that govern modification by UBLs.

Apg8 is a ubiquitin-like protein involved in autophagy in yeast. Apg8 is covalently but transiently attached to membrane lipids through the actions of activating, conjugating, and processing/deconjugating enzymes. The mammalian Apg8 homologues GATE-16, GARARAP, and MAP1-LC3 have been implicated in intra-Golgi transport, receptor sorting, and autophagy, respectively. All are served by a single set of activating and conjugating enzymes. Here we identify a novel mammalian Apg8 homologue, which we name Apg8L, and describe the synthesis of electrophilic probes based on the GATE-16, GARARAP, MAP1-LC3, and Apg8L proteins. These probes not only form specific adducts in crude cell lysates, but also allow identification of the cellular proteases specific for the C termini of these Apg8 homologues. We find a single protease, Apg4B/autophagin-1, capable of acting on GATE-16, GABARAP, MAP1-LC3, and Apg8L. The Apg4B/autophagin-1 protease thus serves as a processing/deconjugating enzyme for these four highly divergent mammalian Apg8 homologues.

The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates the HTLV-1 long terminal repeat and key regulatory proteins involved in inflammation, activation, and proliferation and may induce cell transformation. Tax is also the immunodominant target antigen for cytotoxic T cells in HTLV-1 infection. We found that Tax bound to assembled nuclear proteasomes, but Tax could not be detected in the cytoplasm. Confocal microscopy revealed a partial colocalization of Tax with nuclear proteasomes. As Tax translocated into the nucleus very quickly after synthesis, this process probably takes place prior to and independent of proteasome association. Tax mutants revealed that both the Tax N and C termini play a role in proteasome binding. We also found that proteasomes from Tax-transfected cells had enhanced proteolytic activity on prototypic peptide substrates. This effect was not due to the induction of the LMP2 and LMP7 proteasome subunits. Furthermore, Tax appeared to be a long-lived protein, with a half-life of around 15 h. These data suggest that the association of Tax with the proteasome and the enhanced proteolytic activity do not target Tax for rapid degradation and may not determine its immunodominance.