Recent biological, structural, and technical advances are converging within the HIV-1 vaccine field to harness the power of antibodies for prevention and therapy. Numerous monoclonal antibodies with broad neutralizing activity against diverse HIV-1 isolates have now been identified, revealing at least five sites of vulnerability on the envelope (Env) glycoproteins. While there are practical and technological barriers blocking a clear path from broadly neutralizing antibodies (bNAb) to a protective vaccine, this is not a dead end. Scientists are revisiting old approaches with new technology, cutting new trails through unexplored territory, and paving new roads in the hopes of preventing HIV-1 infection. Other promising avenues to capitalize on the power of bNAbs are also being pursued, such as passive antibody immunotherapy and gene therapy approaches. Moreover, non-neutralizing antibodies have inhibitory activities that could have protective potential, alone or in combination with bNAbs. With a new generation of bNAbs, and a clinical trial that associated antibodies with reduced acquisition, the field is closer than ever to developing strategies to use antibodies against HIV-1.
Voluntary family planning (FP)1 has long been recognized as an essential service that enables individuals and couples to determine whether, when, and how often to have children. The HIV clinical cascade offers women of reproductive age (WRA) a continuous opportunity for integrated care and access to a wide range of voluntary FP services. Strengthening the integration of voluntary FP into HIV services could be particularly impactful for the health of women in sub-Saharan Africa, who experience a double burden of high HIV incidence and high rates of unintended pregnancy.
Background: The restriction factor SAMHD1 regulates intracellular nucleotide level by degrading dNTPs and blocks the replication of retroviruses and DNA viruses in non-cycling cells, like macrophages or dendritic cells. In patients, inactivating mutations in samhd1 are associated with the autoimmune disease Aicardi-Goutières Syndrome (AGS). The accumulation of intracellular nucleic acids derived from endogenous retroelements thriving in the absence of SAMHD1 has been discussed as potential trigger of the autoimmune reaction. In vitro, SAMHD1 has been found to restrict endogenous retroelements, like LINE-1 elements (L1). The mechanism, however, by which SAMHD1 blocks endogenous retroelements, is still unclear. Results: Here, we show that SAMHD1 inhibits the replication of L1 and other endogenous retroelements in cycling cells. By applying GFP- and neomycin-based reporter assays we found that the anti-L1 activity of SAMHD1 is regulated by phosphorylation at threonine 592 (T592). Similar to the block of HIV, the cofactor binding site and the enzymatic active HD domain of SAMHD1 proofed to be essential for restriction of L1 elements. However, phosphorylation at T592 did not correlate with the dNTP hydrolase activity of SAMHD1 in cycling 293T cells suggesting an alternative mechanism of regulation. Interestingly, we found that SAMHD1 binds to ORF2 protein of L1 and that this interaction is regulated by T592 phosphorylation. Together with the finding that the block is also active in cycling cells, our results suggest that the SAMHD1-mediated inhibition of L1 is similar but not identical to HIV restriction. Conclusion: Our findings show conclusively that SAMHD1 restricts the replication of endogenous retroelements in vitro. The results suggest that SAMHD1 is important for maintaining genome integrity and support the idea of an enhanced replication of endogenous retroelements in the absence of SAMHD1 in vivo, potentially triggering autoimmune diseases like AGS. Our analysis also contributes to the better understanding of the activities of SAMHD1 in antiviral defense and nucleotide metabolism. The finding that the phosphorylation of SAMHD1 at T592 regulates its activity against retroelements but not necessarily intracellular dNTP level suggests that the dNTP hydrolase activity might not be the only function of SAMHD1 important for its antiviral activity and for controlling autoimmunity.
Background. The role of suppressive HSV therapy in women coinfected with HSV-2 and HIV-1 taking highly active antiretroviral therapy (HAART) is unclear. Methods. 60 women with HIV-1/HSV-2 coinfection on HAART with plasma HIV-1 viral load (PVL) ≤75 copies/mL were randomized to receive acyclovir (N = 30) or no acyclovir (N = 30). PVL, genital tract (GT) HIV-1, and GT HSV were measured every 4 weeks for one year. Results. Detection of GT HIV-1 was not significantly different in the two arms (OR 1.23, P = 0.67), although this pilot study was underpowered to detect this difference. When PVL was undetectable, the odds of detecting GT HIV were 0.4 times smaller in the acyclovir arm than in the control arm, though this was not statistically significant (P = 0.07). The odds of detecting GT HSV DNA in women receiving acyclovir were significantly lower than in women in the control group, OR 0.38, P < 0.05. Conclusions. Chronic suppressive therapy with acyclovir in HIV-1/HSV-2-positive women on HAART significantly reduces asymptomatic GT HSV shedding, though not GT HIV shedding or PVL. PVL was strongly associated with GT HIV shedding, reinforcing the importance of HAART in decreasing HIV sexual transmission.
Objective. To evaluate whether HIV infected pregnant women with concomitant sexually transmitted infection (STIs) are at increased risk of adverse perinatal and neonatal outcomes. Methods. We conducted a cohort study of HIV positive women who delivered at an inner-city hospital in Atlanta, Georgia, from 2003 to 2013. Demographics, presence of concomitant STIs, prenatal care information, and maternal and neonatal outcomes were collected. The outcomes examined were the association of the presence of concomitant STIs on the risk of preterm birth (PTB), postpartum hemorrhage, chorioamnionitis, preeclampsia, intrauterine growth restriction, small for gestational age, low Apgar scores, and neonatal intensive care admission. Multiple logistic regression was performed to adjust for potential confounders. Results. HIV positive pregnant women with concomitant STIs had an increased risk of spontaneous PTB (odds ratio (OR) 2.11, 95% confidence interval [CI] 1.12-3.97). After adjusting for a history of preterm birth, maternal age, and low CD4+ count at prenatal care entry the association between concomitant STIs and spontaneous PTB persisted (adjusted OR 1.96, 95% CI 1.01-3.78). Conclusions. HIV infected pregnant women with concomitant STIs relative to HIV positive pregnant women without a concomitant STI are at increased risk of spontaneous PTB.
by
Hanna-Mari Stegmann;
Lena Schwarz;
Sarah-Marie Ambiel;
Ina Trotard;
Maud Martin;
Margarethe Burggraf;
Manja Lenzi;
Gina M. Lejk;
Helena Pan;
Xiaoyu Fregoso;
Oliver I. Lim;
Efrem S. Abraham;
Libin Nguyen;
Laura A. Rutsch;
Frank Koenig;
Renate Kim;
Hanna-Mari Baldauf;
Michael Emerman;
Oliver T. Fackler;
Oliver T. Keppler
All rights reserved. Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) o f the incoming viral RNA genome. In this context, dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis. We find that virion-packaged Vpx proteins from a second SIV lineage, SIV of red-capped mangabeys or mandrills (SIVrcm/mnd-2), increased HIV infection in resting CD4 T cells, but not in macrophages, and, unexpectedly, acted in the absence of SAMHD1 degradation, dNTP pool elevation, or changes in SAMHD1 phosphorylation. Vpx rcm/mnd-2 virion incorporation resulted in a dramatic increase of HIV-1 RT intermediates and viral cDNA in infected resting CD4 T cells. These analyses also revealed a barrier limiting HIV-1 infection of resting CD4 T cells at the level of nuclear import. Single amino acid changes in the SAMHD1-degrading Vpx mac239 allowed it to enhance early postentry steps in a Vpx rcm/mnd-2-like fashion. Moreover, Vpx enhanced HIV-1 infection of SAMHD1-deficient resting CD4 T cells of a patient with Aicardi- Goutières syndrome. These results indicate that Vpx, in addition to SAMHD1, overcomes a previously unappreciated restriction for lentiviruses at the level of RT that acts independently of dNTP concentrations and is specific to resting CD4 T cells.
by
Joseph T. King;
Adam J. Gordon;
Melissa F. Perkal;
Stephen Crystal;
Ronnie A. Rosenthal;
Maria C. Rodriguez-Barradas;
Adeel A. Butt;
Cynthia L. Gibert;
David Rimland;
Michael S. Simberkoff;
Amy C. Justice
STUDY DESIGN.: Retrospective analysis of nationwide Veterans Health Administration clinical and administrative data. OBJECTIVE.: Examine the association between HIV infection and the rate of spine surgery for degenerative spine disease. SUMMARY OF BACKGROUND DATA.: Combination antiretroviral therapy has prolonged survival in HIV-infected patients, increasing the prevalence of chronic conditions such as degenerative spine disease that may require spine surgery. METHODS.: We studied all HIV-infected patients under care in the Veterans Health Administration from 1996 to 2008 (n = 40,038) and uninfected comparator patients (n = 79,039) matched on age, sex, race, year, and geographic region. The primary outcome was spine surgery for degenerative spine disease, defined by International Classification of Diseases, Ninth Revision procedure and diagnosis codes. We used a multivariate Poisson regression to model spine surgery rates by HIV infection status, adjusting for factors that might affect suitability for surgery (demographics, year, comorbidities, body mass index, combination antiretroviral therapy, and laboratory values). RESULTS.: Two hundred twenty-eight HIV-infected and 784 uninfected patients underwent spine surgery for degenerative spine disease during 700,731 patient-years of follow-up (1.44 surgeries per 1000 patient-years). The most common procedures were spinal decompression (50%) and decompression and fusion (33%); the most common surgical sites were the lumbosacral (50%) and cervical (40%) spine. Adjusted rates of surgery were lower for HIV-infected patients (0.86 per 1000 patient-years of follow-up) than for uninfected patients (1.41 per 1000 patient-years; incidence rate ratio 0.61, 95% confidence interval: 0.51-0.74, P < 0.001). Among HIV-infected patients, there was a trend toward lower rates of spine surgery in patients with detectable viral load levels (incidence rate ratio 0.76, 95% confidence interval: 0.55-1.05, P = 0.099). CONCLUSION.: In the Veterans Health Administration, HIV-infected patients experience significantly reduced rates of surgery for degenerative spine disease. Possible explanations include disease prevalence, emphasis on treatment of nonspine HIV-related symptoms, surgical referral patterns, impact of HIV on surgery risk-benefit ratio, patient preferences, and surgeon bias.
Objective:
To describe system failures potentially contributing to perinatal HIV transmission in the state of Georgia, United States, between 2005 and 2012.
Design:
A retrospective chart review of antenatal and postnatal records of HIV-infected infants between 1 January 2005 and 31 December 2012.
Methods:
Study participants included all HIV-infected infants referred for specialized management to the Ponce Family and Youth Clinic within Grady Health Systems in Atlanta. Main outcomes included identification of maternal, perinatal, and neonatal risk factors associated with vertical transmission.
Results:
Twenty-seven cases were identified; 89% of mothers were African–American between 16 and 30 years of age. Seventy-four percent of women knew their HIV status prior to pregnancy, 44% had no prenatal care, and 52% did not receive combination antiretroviral therapy during pregnancy or intrapartum zidovudine. HIV-1 RNA near the time of delivery was available in only 10 of 27 mothers, and of those, only three had an undetectable HIV-1 RNA level. Caesarean section was performed in 70% of women. Of the 27 children, the mean gestational age was 37 (SD: 2.9) weeks, with 33% requiring neonatal ICU admission. Fifty-nine percent were men, and only 67% received postnatal zidovudine prophylaxis.
Conclusion:
Mother-to-child transmission of HIV continues to occur in Georgia at unacceptable levels. Increased education with adherence to existing national guidelines, as well as coordinated efforts between healthcare and public health providers to improve linkage and retention in medical care are urgently needed to prevent further vertical transmission events in Georgia.
Background: Monetary delay discounting is a measure of impulsivity associated with substance use and abuse, problem gambling, and other health-related outcomes. More recently, delay discounting has been shown to be associated with risky sexual behavior. We analyzed survey data from men who have sex with men who completed a monetary discounting task and reported sexual behaviors in the previous 12 months. Findings: Monetary delay discounting was associated with condomless anal intercourse among young (18–24 years), but not older, men who have sex with men. Conclusions: Monetary delay discounting may identify young men at increased risk of engaging in HIV risk behaviors.
by
Stefanie Kretschmer;
Christine Wolf;
Nadja Koenig;
Wolfgang Staroske;
Jochen Guck;
Martin Haeusler;
Hella Luksch;
Laura A. Nguyen;
Baek Kim;
Dimitra Alexopoulou;
Andreas Dahl;
Alexander Rapp;
M. Cristina Cardoso;
Anna Shevchenko;
Min Ae Lee-Kirsch
Objectives: The HIV restriction factor, SAMHD1 (SAM domain and HD domain-containing protein 1), is a triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs). Mutations in SAMHD1 cause Aicardi-Goutières syndrome (AGS), an inflammatory disorder that shares phenotypic similarity with systemic lupus erythematosus, including activation of antiviral type 1 interferon (IFN). To further define the pathomechanisms underlying autoimmunity in AGS due to SAMHD1 mutations, we investigated the physiological properties of SAMHD1.
Methods: Primary patient fibroblasts were examined for dNTP levels, proliferation, senescence, cell cycle progression and DNA damage. Genome-wide transcriptional profiles were generated by RNA sequencing. Interaction of SAMHD1 with cyclin A was assessed by coimmunoprecipitation and fluorescence cross- correlation spectroscopy. Cell cycle-dependent phosphorylation of SAMHD1 was examined in synchronised HeLa cells and using recombinant SAMHD1. SAMHD1 was knocked down by RNA interference.
Results: We show that increased dNTP pools due to SAMHD1 deficiency cause genome instability in fibroblasts of patients with AGS. Constitutive DNA damage signalling is associated with cell cycle delay, cellular senescence, and upregulation of IFN-stimulated genes. SAMHD1 is phosphorylated by cyclin A/cyclindependent kinase 1 in a cell cycle-dependent manner, and its level fluctuates during the cell cycle, with the lowest levels observed in G 1 /S phase. Knockdown of SAMHD1 by RNA interference recapitulates activation of DNA damage signalling and type 1 IFN activation.
Conclusions: SAMHD1 is required for genome integrity by maintaining balanced dNTP pools. dNTP imbalances due to SAMHD1 deficiency cause DNA damage, leading to intrinsic activation of IFN signalling. These findings establish a novel link between DNA damage signalling and innate immune activation in the pathogenesis of autoimmunity.