Incidence and prevalence of intrasubtype HIV-1 dual infection in at-risk men in the United States.
ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) dual infection (DI) has been associated with decreased CD4 T-cell counts and increased viral loads; however, the frequency of intrasubtype DI is poorly understood. We used ultradeep sequencing (UDS) to estimate the frequency of DI in a primary infection cohort of predominantly men who have sex with men (MSM).?HIV-1 genomes from longitudinal blood samples of recently infected, therapy-naive participants were interrogated with UDS. DI was confirmed when maximum sequence divergence was excessive and supported by phylogenetic analysis. Coinfection was defined as DI at baseline; superinfection was monoinfection at baseline and DI at a later time point.?Of 118 participants, 7 were coinfected and 10 acquired superinfection. Superinfection incidence rate was 4.96 per 100 person-years (95% confidence interval [CI], 2.67-9.22); 6 occurred in the first year and 4 in the second. Overall cumulative prevalence of intrasubtype B DI was 14.4% (95% CI, 8.6%-22.1%). Primary HIV-1 incidence was 4.37 per 100 person-years (95% CI, 3.56-5.36).?Intrasubtype DI was frequent and comparable to primary infection rates among MSM in San Diego; however, superinfection rates declined over time. DI is likely an important component of the HIV epidemic dynamics, and development of stronger immune responses to the initial infection may protect from superinfection.
Project description:HIV superinfection describes the sequential infection of an individual with two or more unrelated HIV strains. Intersubtype superinfection has been shown to cause a broader and more potent heterologous neutralizing antibody response when compared to singly infected controls, yet the effects of intrasubtype superinfection remain controversial. Longitudinal samples were analyzed phylogenetically for pol and env regions using Next-Generation Sequencing and envelope cloning. The impact of CRF02_AG intrasubtype superinfection was assessed for heterologous neutralization and antibody binding responses. We compared two cases of CRF02_AG intrasubtype superinfection that revealed complete replacement of the initial virus by superinfecting CRF02_AG variants with signs of recombination. NYU6564, who became superinfected at an early time point, exhibited greater changes in antibody binding profiles and generated a more potent neutralizing antibody response post-superinfection compared to NYU6501. In contrast, superinfection occurred at a later time point in NYU6501 with strains harboring significantly longer V1V2 regions with no observable changes in neutralization patterns. Here we show that CRF02_AG intrasubtype superinfection can induce a cross-subtype neutralizing antibody response, and our data suggest timing and/or superinfecting viral envelope characteristics as contributing factors. These results highlight differential outcomes in intrasubtype superinfection and provide the first insight into cases with CRF02_AG, the fourth most prevalent HIV-1 strain worldwide.
Project description:Understanding whether the neutralizing antibody (NAb) response impacts HIV-1 superinfection and how superinfection subsequently modulates the NAb response can help clarify correlates of protection from HIV exposures and better delineate pathways of NAb development. We examined associations between the development of NAb and the occurrence of superinfection in a well-characterized, antiretroviral therapy (ART)-naive, primary infection cohort of men who have sex with men. Deep sequencing was applied to blood plasma samples from the cohort to detect cases of superinfection. We compared the NAb activity against autologous and heterologous viruses between 10 participants with intrasubtype B superinfection and 19 monoinfected controls, matched to duration of infection and risk behavior. Three to 6 months after primary infection, individuals who would later become superinfected had significantly weaker NAb activity against tier 1 subtype B viruses (P = 0.003 for SF-162 and P = 0.017 for NL4-3) and marginally against autologous virus (P = 0.054). Lower presuperinfection NAb responses correlated with weaker gp120 binding and lower plasma total IgG titers. Soon after superinfection, the NAb response remained lower, but between 2 and 3 years after primary infection, NAb levels strengthened and reached those of controls. Superinfecting viruses were typically not susceptible to neutralization by presuperinfection plasma. These observations suggest that recently infected individuals with a delayed NAb response against primary infecting and tier 1 subtype B viruses are more susceptible to superinfection.IMPORTANCE Our findings suggest that within the first year after HIV infection, a relatively weak neutralizing antibody response against primary and subtype-specific neutralization-sensitive viruses increases susceptibility to superinfection in the face of repeated exposures. As natural infection progresses, the immune response strengthens significantly in some superinfected individuals. These findings will inform HIV vaccine design by providing testable correlates of protection from initial HIV infection.
Project description:Considerable numbers of HIV-1-infected men who have sex with men (MSM) show a relatively rapid disease progression in China; however, the cause remains elusive. HIV-1 dual infection was reported to occur commonly among the MSM population, and its contribution to clinical prognosis remains controversial. We investigated the occurrence and impact on disease progression of dual infection in a prospective MSM cohort in China.Sixty-four HIV-1 early-infected participants were longitudinally followed up for 2 years. Deep sequencing was used as dual-infection screening. CD4 T-cell counts and HIV-1 viral load were compared between coinfection and single-infection participants and pre- versus post-superinfection.Eight coinfected participants and 10 superinfected participants were identified, including 9 participants with intersubtype and 9 with intrasubtype dual infections. The prevalence of coinfection was 13.1%, with a superinfection incidence of 15.6%. Coinfection participants showed lower CD4 T-cell counts at 120 days after infection (P = 0.042) and a higher viral set point tendency (P = 0.053) as compared with single-infection participants. Kaplan-Meier analysis showed that the time for the viral load to increase to above 4 log10 copies per milliliter was shorter in coinfection participants than in single-infection participants (P < 0.001). After superinfection, the median CD4 T-cell count decreased from 635 to 481 cells/?L (P = 0.027).The occurrence of dual infection among Chinese MSM is relatively high, and HIV-1 dual infection might contribute to rapid disease progression seen in the MSM population.
Project description:Human immunodeficiency virus (HIV) superinfection has been documented in high-risk individuals; however, the rate of superinfection among HIV-infected individuals within a general population remains unknown.A novel next-generation ultra-deep sequencing technique was utilized to determine the rate of HIV superinfection in a heterosexual population by examining two regions of the viral genome in longitudinal samples from recent HIV seroconverters (n=149) in Rakai District, Uganda.The rate of superinfection was 1.44 per 100 person years (PYs) (95% confidence interval [CI], .4-2.5) and consisted of both inter- and intrasubtype superinfections. This was compared to primary HIV incidence in 20 220 initially HIV-negative individuals in the general population in Rakai (1.15 per 100 PYs; 95% CI, 1.1-1.2; P= .26). Propensity score matching (PS) was used to control for differences in sociodemographic and behavioral characteristics between the HIV-positive individuals at risk for superinfection and the HIV-negative population at baseline and follow-up. After PS matching, the estimated rate of primary incidence was 3.28 per 100 PYs (95% CI, 2.0-5.3; P = .07) controlling for baseline differences and 2.51 per 100 PYs (95% CI, 1.5-4.3; P = .24) controlling for follow-up differences.This suggests that the rate of HIV superinfection in a general population is substantial, which could have a significant impact on future public health and HIV vaccine strategies.
Project description:Recombinant human immunodeficiency virus type 1 (HIV-1) strains containing sequences from different viral genetic subtypes (intersubtype) and different lineages from within the same subtype (intrasubtype) have been observed. A consequence of recombination can be the distortion of the phylogenetic signal. Several intersubtype recombinants have been identified; however, less is known about the frequency of intrasubtype recombination. For this study, near-full-length HIV-1 subtype C genomes from 270 individuals were evaluated for the presence of intrasubtype recombination. A sliding window schema (window, 2 kb; step, 385 bp) was used to partition the aligned sequences. The Shimodaira-Hasegawa test detected significant topological incongruence in 99.6% of the comparisons of the maximum-likelihood trees generated from each sequence partition, a result that could be explained by recombination. Using RECOMBINE, we detected significant levels of recombination using five random subsets of the sequences. With a set of 23 topologically consistent sequences used as references, bootscanning followed by the interactive informative site test defined recombination breakpoints. Using two multiple-comparison correction methods, 47% of the sequences showed significant evidence of recombination in both analyses. Estimated evolutionary rates were revised from 0.51%/year (95% confidence interval [CI], 0.39 to 0.53%) with all sequences to 0.46%/year (95% CI, 0.38 to 0.48%) with the putative recombinants removed. The timing of the subtype C epidemic origin was revised from 1961 (95% CI, 1947 to 1962) with all sequences to 1958 (95% CI, 1949 to 1960) with the putative recombinants removed. Thus, intrasubtype recombinants are common within the subtype C epidemic and these impact analyses of HIV-1 evolution.
Project description:HIV superinfection, which occurs when a previously infected individual acquires a new distinct HIV strain, has been described in a number of populations. Previous methods to detect superinfection have involved a combination of labor-intensive assays with various rates of success. We designed and tested a next-generation sequencing (NGS) protocol to identify HIV superinfection by targeting two regions of the HIV viral genome, p24 and gp41. The method was validated by mixing control samples infected with HIV subtype A or D at different ratios to determine the inter- and intrasubtype sensitivity by NGS. This amplicon-based NGS protocol was able to consistently identify distinct intersubtype strains at ratios of 1% and intrasubtype variants at ratios of 5%. By using stored samples from the Rakai Community Cohort Study (RCCS) in Uganda, 11 individuals who were HIV seroconcordant but virally unlinked from their spouses were then tested by this method to detect superinfection between 2002 and 2005. Two female cases of HIV intersubtype superinfection (18.2%) were identified. These results are consistent with other African studies and support the hypothesis that HIV superinfection occurs at a relatively high rate. Our results indicate that NGS can be used for detection of HIV superinfection within large cohorts, which could assist in determining the incidence and the epidemiologic, virologic, and immunological correlates of this phenomenon.
Project description:In this study, the prevalence of HIV-1 CRF01_AE intrasubtype recombinants in China is estimated and their contributions to the epidemic are explored.Available HIV-1 complete genomes of CRF01_AE were retrieved from the HIV database. The two alignments were evaluated with RDP3. Recombinants were defined as cases in which the recombination signal was supported by at least 3 methods with P-values of ?0.05 after Bonferroni correction for multiple comparisons implemented in RDP3. Phylogenetic analysis was performed to further investigate the role of intrasubtype recombinants in epidemics.Here, 124 out of the 339 sequences from around the world (36.6 %) showed significant evidence of recombination. Here, 84 of these recombinants were from China, accounting for 54.9 % of local total sequences (84 out of 153). The results indicated non-negligible levels of intrasubtype recombination. Subsequent phylogenetic analysis indicated that a considerable proportion of CRF01_AE strains in China originated from circulating intrasubtype recombinant forms. Three large, well-supported intrasubtype recombinants clusters were identified here. Through a survey of risk factors and sampling cities and provinces, cluster I and cluster II were found to be prevalent primarily among men who have sex with men in major northern cities. Cluster III was prevalent among heterosexuals and intravenous drug users in southern and southwestern provinces.The current work highlighted the remarkable prevalence of intrasubtype recombination within the CRF01_AE epidemic and emphasized the value of intrasubtype recombinants, which came to circulate in the same manner as intersubtype recombinants.
Project description:Background:Little is known about the hepatitis C virus (HCV) epidemic among HIV-infected men who have sex with men (HIV+ MSM) in the United States. In this study, we aimed to determine the incidence of primary HCV infection among HIV+ MSM in San Diego, California. Methods:We performed a retrospective cohort analysis of HCV infection among HIV+ MSM attending 2 of the largest HIV clinics in San Diego. Incident HCV infection was assessed among HIV+ MSM with a negative anti-HCV test and subsequent HCV test between 2000 and 2017, with data censored to 2015. HCV reinfection was assessed among HIV+ MSM successfully treated for HCV between 2008 and 2015. Infection/reinfection rates were calculated using person-time methods. Results:Among 3068 initially HCV-seronegative HIV+ MSM, 178 new infections occurred over 15 796 person-years, giving an incidence of 1.13 per 100 person-years (/100py; 95% confidence interval [CI], 0.97-1.31). Incidence was stable from 2000 to 2014 (0.83/100py; 95% CI, 0.41-1.48), with an increase to 3.01/100py (95% CI, 1.97-4.42) in 2015 (P = .02). Among 43 successfully treated patients, 3 were reinfected. Conclusions:HCV incidence is high among HIV+ MSM in San Diego, with evidence suggesting a recent increase in 2015. Strong HCV testing guidelines and active prevention efforts among HIV+ MSM are urgently needed that include rapid diagnosis, treatment, and risk reduction.
Project description:<h4>Introduction</h4>The aim of this study was to determine the risk factors for HIV infection and the incidence in men who have sex with men (MSM). It is important to identify subgroups of MSM in which preventive interventions such as pre-exposure prophylaxis (PrEP) offered at the time of their last negative test would be considered cost-effective.<h4>Methods</h4>We conducted a retrospective cohort study of MSM attending Melbourne Sexual Health Centre (MSHC) during 2007-2013 with at least two HIV tests within 12 months of each other. Demographic characteristics, sexual and other behaviours, and bacterial sexually transmitted infection (STI) diagnoses were extracted from the date of the last negative HIV test. HIV incidence rate (IR) per 100 person-years for each risk factor was calculated.<h4>Results</h4>Of the 13907 MSM who attended MSHC, 5256 MSM had at least two HIV tests and were eligible, contributing 6391 person-years follow-up. 81 new HIV diagnoses were identified within 12 months of an HIV negative test with an incidence of 1.3 (95% CI: 1.0-1.6) per 100 person-years. Significant associations with subsequent HIV infection were: rectal gonorrhea (HIV IR: 3.4 95% CI: 2.1-5.2), rectal chlamydia (HIV IR: 2.6 95% CI: 1.7-3.7), inconsistent condom use (HIV IR: 2.1 95% CI: 1.6-2.7), use of post-exposure prophylaxis (HIV IR: 2.3 95% CI: 1.7-3.1), and injecting drug use (HIV IR: 8.5 95% CI: 3.4-17.5).<h4>Conclusion</h4>The incidence of HIV was above 2.0% in subgroups of MSM with specific characteristics at the last HIV negative test. PrEP is considered cost effective at this incidence and could potentially be used along with other preventive interventions for these individuals in more than half of the population.
Project description:The aim of this study was to characterize the demographic, behavioural, clinical and immunogenetic determinants of HIV-1 superinfection in a high-risk cohort of MSM.A retrospective cohort study of prospectively followed MSM.Ninety-eight MSM with acute or early HIV-1 monoinfection were followed for a median of 15.6 months. Demographic and human leukocyte antigen (HLA) genotype data were collected at enrolment. Sexual behaviour, clinical and the infection status (monoinfection or superinfection) data were recorded at each visit (at enrolment and thereafter at a median of 4.2-month intervals). HIV-1 superinfection risk was determined by Cox regression and Kaplan-Meier survival analysis.Ten individuals (10.2%) had superinfection during follow-up. Cox regression did not show significantly increased superinfection risk for individuals with an increased amount of condomless anal intercourse, lower CD4 T-cell count or higher viral load, but higher number of sexual contacts demonstrated a trend towards significance [hazard ratio, 4.74; 95% confidence interval (95% CI), 0.87-25.97; P?=?0.073]. HLA-A*29 (hazard ratio, 4.10; 95% CI, 0.88-14.76; P?=?0.069), HLA-B*35 (hazard ratio, 4.64; 95% CI, 1.33-18.17; P?=?0.017), HLA-C*04 (hazard ratio, 5.30; 95% CI, 1.51-20.77; P?=?0.010), HLA-C*16 (hazard ratio, 4.05; 95% CI, 0.87-14.62; P?=?0.071), HLA-DRB1*07 (hazard ratio, 3.29; 95% CI, 0.94-12.90; P?=?0.062) and HLA-DRB1*08 (hazard ratio, 15.37; 95% CI, 2.11-79.80; P?=?0.011) were associated with an increased risk of superinfection at ??=?0.10, whereas HLA-DRB1*11 was associated with decreased superinfection risk (hazard ratio, 0.13; 95% CI, 0.00-1.03; P?=?0.054).HLA genes may, in part, elucidate the genetic basis of differential superinfection risk, and provide important information for the development of efficient prevention and treatment strategies of HIV-1 superinfection.