Underestimated effect of intragenic HIV-1 DNA methylation on viral transcription in infected individuals

Background: The HIV-1 proviral genome harbors multiple CpG islands (CpGIs), both in the promoter and intragenic regions. DNA methylation in the promoter region has been shown to be heavily involved in HIV-1 latency regulation in cultured cells. However, its exact role in proviral transcriptional regulation in infected individuals is poorly understood or characterized. Moreover, methylation at intragenic CpGIs has never been studied in depth. Results: A large, well-characterized HIV-1 patient cohort (n = 72), consisting of 17 long-term non-progressors and 8 recent seroconverters (SRCV) without combination antiretroviral therapy (cART), 15 early cART-treated, and 32 late cART-treated patients, was analyzed using a next-generation bisulfite sequencing DNA methylation method. In general, we observed low level of promoter methylation and higher levels of intragenic methylation. Additionally, SRCV showed increased promoter methylation and decreased intragenic methylation compared with the other patient groups. This data indicates that increased intragenic methylation could be involved in proviral transcriptional regulation. Conclusions: Contrasting in vitro studies, our results indicate that intragenic hypermethylation of HIV-1 proviral DNA is an underestimated factor in viral control in HIV-1-infected individuals, showing the importance of analyzing the complete proviral genome in future DNA methylation studies

Highlights from the 9th IAS conference on HIV science, 23-26 July 2017, Paris, France

The 9th International AIDS Society Conference on HIV Science (IAS 2017) took place at the Palais des Congrès, in Paris, France, from 23 to 26 July 2017, chaired by Linda-Gail Bekker and Jean-François Delfraissy. It was organised by the International AIDS Society (IAS) in partnership with ANRS (the French national agency for research on AIDS and viral hepatitis), bringing together more than 6000 leading scientists, researchers and HIV professionals from around the world. The Conference featured more than 1800 abstracts selected for oral and poster presentations out of over 4300 submissions, in addition to plenary sessions and satellite symposia. Prevention was high on the agenda of this year's Conference. Data relevant to children, adolescents and adults with HIV on recent advances in the understanding of viral–host interactions, targeting of the HIV reservoir, new oral and long-acting antiretroviral drugs, strategies for simplification of treatment regimens, immune-based therapies, pre-exposure prophylaxis (PrEP) to HIV, prevention of mother-to-child transmission, prophylactic and therapeutic vaccines, as well as comorbidities including hepatitis, were presented with an emphasis on translating science into practice and policies

Impact of a decade of successful antiretroviral therapy initiated at HIV-1 seroconversion on blood and mucosal reservoirs

Persistent reservoirs remain the major obstacles to achieve an HIV-1 cure. Prolonged early antiretroviral therapy (ART) may reduce the extent of reservoirs and allow for virological control after ART discontinuation. We compared HIV-1 reservoirs in a cross-sectional study using polymerase chain reaction-based techniques in blood and tissue of early-treated seroconverters, late-treated patients, ART-naïve seroconverters, and long-term non-progressors (LTNPs) who have spontaneous virological control without treatment. A decade of early ART reduced the total and integrated HIV-1 DNA levels compared with later treatment initiation, but not reaching the low levels found in LTNPs. Total HIV-1 DNA in rectal biopsies did not differ between cohorts. Importantly, lower viral transcription (HIV-1 unspliced RNA) and enhanced immune preservation (CD4/CD8), reminiscent of LTNPs, were found in early compared to late-treated patients. This suggests that early treatment is associated with some immunovirological features of LTNPs that may improve the outcome of future interventions aimed at a functional cure

Highlights from the 24th conference on retroviruses and opportunistic infections, 13-16 February 2017, Seattle, Washington, USA

From the 13th to 16th February 2017, researchers from around the world convened for the 24th annual Conference on Retroviruses and Opportunistic Infections (CROI) at the Washington State Convention Center in Seattle, Washington. The conference was organised by the International Antiviral Society-USA (IAS-USA) in partnership with the CROI Foundation. The conference included over 1000 oral and poster presentations of peer-reviewed original research as well as lectures and symposia featuring insights from leading basic, translational and clinical researchers. Highlighted here are key data presented at the conference

Symptomatic Primary Infection Due to Human Immunodeficiency Virus Type 1: Review of 31 Cases

In this series of 31 patients with acute infection due to human immunodeficiency virus (HIV) type 1, the male-to-female ratio was 3.4:1 and the mean age was 31.3 years. Sexual transmission accounted for 83.9% of cases; 45.2% of the patients were homosexual and 38.7% were heterosexual. The mean duration of symptoms and signs was 21 days (range, 5-60 days). Fever (87.1%) and skin rash (67.7%) were most commonly reported. Physical examination findings were abnormal for 96% of the patients; the oral cavity (76.7%) and the skin (73.3%) were the most frequently involved sites. Thirteen of 25 patients with sexually acquired infection had genital or oral ulcers, whereas five intravenous drug users had none (P = .052). Thrombocytopenia was the most common hematologic abnormality and was detected in 17 of 23 patients tested. P24 antigenemia, an initially negative screening test for HIV antibody, and a low CD4+ lymphocyte count were noted in 23 of 29, 23 of 30, and 14 of 21 tested patients, respectivel

Severity and Prognosis of Acute Human Immunodeficiency Virus Type 1 Illness: A Dose-Response Relationship

This study examined the relationship between the severity of acute human immunodeficiency virus type 1 (HIV-1) illness and disease progression and death. The population included 218 patients with acute HIV-1 illness and 41 asymptomatic patients who underwent HIV-1 seroconversion; the patients were followed up prospectively. We analyzed progression to Centers for Disease Control and Prevention clinical categories B and C (AIDS-defining conditions) and death according to an additive clinical score (CS) based on six predictive clinical features at the time of acute HIV-1 infection. Compared with patients with a CS of 0 (asymptomatic patients), those with a CS of 3-4 and 5-6 had faster progression to category B disease (adjusted hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.01-1.92; and HR, 1.80; 95% CI, 1.34-2.40; respectively); those with a CS of 5-6 had faster progression to category C disease (HR, 1.37; 95% CI, 1.01-1.89) and death (HR, 2.05; 95% CI, 1.27-3.32). Thus, the number of symptoms and signs at the time of acute HIV-1 illness affects disease progression and survival, even in symptomatic patients who have undergone seroconversio

Acute Human Immunodeficiency Virus Type 1 Disease as a Mononucleosis-Like Illness: Is the Diagnosis Too Restrictive?

The purpose of this study was to describe the frequency and duration of clinical features at the time of acute human immunodeficiency virus type 1 (HIV-1) disease in 218 patients with documented symptomatic primary HIV-1 infection. The mean duration of acute HIV-1 disease was 25.1 days (median, 20.0 days) and did not differ by gender, age, and risk factor. The frequency and mean duration of clinical features occurring in >50% of patients were as follows: fever, 77.1% and 16.9 days; lethargy, 65.6% and 23.7 days; cutaneous rash, 56.4% and 15 days; myalgia, 54.6% and 17.7 days; and headache, 50.9% and 25.8 days. Only 15.6% of patients presented with a typical mononucleosis-like illness (MLI) defined as fever, pharyngitis or sore throat, and cervical adenopathy, and 10% had no features of an MLI. A meningitis-like syndrome occurred in 20 patients (9.2%). Acute HIV-1 disease is more diverse than previously reported, and the absence of fever or other MLI features does not rule out acute HIV-1 diseas

Early treated HIV-1 positive individuals demonstrate similar restriction factor expression profile as long-term non-progressors

Background: A wide range of host restriction factors (RF) become upregulated upon HIV-1 infection to suppress viral infectivity and may aid viremic control in vivo. This cross-sectional study evaluated HIV-1 RFs and dependency factors in HIV infected individuals with progressive or non-progressive infection, as well as in early and late treated cohorts that exhibit different viro-immunological profiles due to differences in timing of treatment-initiation. Methods: The expression profile of IFIT1, MX1, APOBEC3G, SAMHD1, BST2 (encoding TETHERIN), TRIM5, MX2, SLFN11, PAF1, PSIP1 (encoding LEDGF/p75), and NLRX1 was measured by qPCR in 104 HIV-1 positive individuals: seroconverters (SRCV; n =19), long term non-progressors (LTNP; n =17), viremic progressors (VP; n =12), patients treated during seroconversion (Early treated; n =24) or chronic infection (Late treated; n =32), and non-infected controls. Findings: Expression levels of early treated HIV-1 positive individuals were significantly upregulated in comparison to late treated patients (IFIT1: p=0.0003; MX1: p=0.008; APOBEC3G: p=0.002; SAMHD1: p=0.0008; SLFN11: p<0.0001; BST2: p<0.0001). Similarly, SLFN11, BST2, and SAMHD1 were highly expressed in LTNPs at comparable levels as in early treated HIV-1 positive individuals. Furthermore, SLFN11 and SAMHD1 expression negatively correlated with total and integrated HIV-1 DNA levels. Interpretation: Early treatment initiation maintains initial RF elevation even after a decade of ART. Elevated expression of SLFN11, BST2, and SAMHD1 in LTNP and early treated subjects implies that these RFs may be associated with spontaneous virological control