The HIV capsid mimics karyopherin engagement of FG-nucleoporins.

HIV can infect non-dividing cells because the viral capsid can overcome the selective barrier of the nuclear pore complex and deliver the genome directly into the nucleus1,2. Remarkably, the intact HIV capsid is more than 1,000 times larger than the size limit prescribed by the diffusion barrier of the nuclear pore3. This barrier in the central channel of the nuclear pore is composed of intrinsically disordered nucleoporin domains enriched in phenylalanine-glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins and their bound cargoes solubilize in this phase to drive nucleocytoplasmic transport4. By performing an in vitro dissection of the nuclear pore complex, we show that a pocket on the surface of the HIV capsid similarly interacts with FG motifs from multiple nucleoporins and that this interaction licences capsids to penetrate FG-nucleoporin condensates. This karyopherin mimicry model addresses a key conceptual challenge for the role of the HIV capsid in nuclear entry and offers an explanation as to how an exogenous entity much larger than any known cellular cargo may be able to non-destructively breach the nuclear envelope.

New indicators for delay in initiation of antiretroviral treatment: estimates for Cameroon.

OBJECTIVE: To propose two new indicators for monitoring access to antiretroviral treatment (ART) for human immunodeficiency virus (HIV); (i) the time from HIV seroconversion to ART initiation, and (ii) the time from ART eligibility to initiation, referred to as delay in ART initiation. To estimate values of these indicators in Cameroon. METHODS: We used linear regression to model the natural decline in CD4+ T-lymphocyte (CD4+ cell) numbers in HIV-infected individuals over time. The model was fitted using data from a cohort of 351 people in Côte d'Ivoire. We used the model to estimate the time from seroconversion to ART initiation and the delay in ART initiation in a representative sample of 4154 HIV-infected people who started ART in Cameroon between 2007 and 2010. FINDINGS: In Cameroon, the median CD4+ cell counts at ART initiation increased from 140 cells/µl (interquartile range, IQR: 66 to 210) in 2007-2009 to 163 cells/µl (IQR: 73 to 260) in 2010. The estimated average time from seroconversion to ART initiation decreased from 10.4 years (95% confidence interval, CI: 10.3 to 10.5) to 9.8 years (95% CI: 9.6 to 10.0). Delay in ART initiation increased from 3.4 years (95% CI: 3.1 to 3.7) to 5.8 years (95% CI: 5.6 to 6.2). CONCLUSION: The estimated time to initiate ART and the delay in ART initiation indicate that progress in Cameroon is insufficient. These indicators should help monitor whether public health interventions to accelerate ART initiation are successful.

The undiagnosed HIV epidemic in France and its implications for HIV screening strategies.

BACKGROUND: Describing the undiagnosed HIV-infected population is essential for guiding HIV screening policy, implementing interventions, and resource planning. METHODS: We used French national HIV surveillance data and a back-calculation approach to estimate the number of undiagnosed HIV-infected individuals in France and the distribution of time since HIV infection among undiagnosed individuals. We also used data on CD4⁺ cell count decline to assess the CD4⁺ cell count distribution among undiagnosed individuals. RESULTS: We estimated that 29,000 [95% confidence interval (CI): 24,200-33,900] individuals were living with undiagnosed HIV infection at the end of 2010. Of these, 28.7% (95% CI: 27.1-30.4) were infected less than a year ago, 16.4% (95% CI: 15.0-17.8) more than 5 years ago, and 59.6% (95% CI: 59.2-59.8) were eligible for antiretroviral treatment (CD4⁺ cell count less than 500 cells/µl) according to the 2010 French guidelines. Men represented 70.0% of the undiagnosed HIV-infected individuals and had lower CD4⁺ cell counts than women. The numbers of undiagnosed infections in MSM, non-French national heterosexuals, and French national heterosexuals were similar (9200, 9300, 10,000, respectively). However, because of differences in group size, undiagnosed HIV prevalence varied significantly between these groups (2.95, 0.36, 0.03%, respectively; P less than 0.001). CONCLUSION: Our findings suggest that many undiagnosed HIV-infected individuals were eligible for treatment and, thus, lack of HIV diagnosis is a lost chance for them; many more heterosexuals than MSM will need to be tested to find those undiagnosed; and universal screening of men may be cost-effective, especially in the areas most affected by the epidemic, such as the Paris region.

Factors associated with late antiretroviral therapy initiation in Cameroon: a representative multilevel analysis.

OBJECTIVES: Many people living with HIV/AIDS in resource-limited settings begin antiretroviral therapy (ART) at low CD4 counts. Here, we investigated the simultaneous effect of individual-, facility- and regional-level factors on late ART initiation. METHODS: We conducted a survey in a nationally representative sample of 55 HIV treatment facilities in Cameroon. Medical records of 4935 patients >15 years of age who initiated ART in the month of October during the period 2007-10 were reviewed to gather individual characteristics. Late ART initiation was defined as CD4 count ≤ 100 cells/mm(3). Facility- and regional-level characteristics were also collected. Two-level regression logistic models were used to identify factors associated with late ART initiation. RESULTS: Late ART initiation was associated with being a male younger than 45 years versus female younger than 45 years [adjusted OR (AOR) = 1.5, 95% CI: 1.3-1.7] and initiating ART in the period 2007-09 versus 2010 (AOR = 1.2, 95% CI: 1.0-1.4). Late initiation was more likely in central than in district hospitals (AOR = 1.3, 95% CI: 1.1-1.6) and in hospitals without a mother-to-child transmission programme (AOR = 1.9, 95% CI: 1.3-2.8). Living in a region with a higher comprehensive knowledge of HIV/AIDS was associated with not initiating ART late (AOR = 0.8, 95% CI: 0.6-1.0). CONCLUSIONS: This study shows that risk factors associated with late ART initiation operate at multiple levels and that multilevel interventions are therefore necessary to promote earlier HIV testing and treatment.

New method for estimating HIV incidence and time from infection to diagnosis using HIV surveillance data: results for France.

OBJECTIVE: To estimate HIV incidence and time between HIV infection and diagnosis of infection. DESIGN: We devised a new model for estimating the incidence of HIV infection and the time between infection and diagnosis from HIV surveillance data. Our approach takes into account temporal changes in HIV test-seeking behaviors and requires few data on individuals newly diagnosed with HIV (i.e. date of diagnosis and clinical status at diagnosis). Using our new approach, we analyzed data for patients newly diagnosed with HIV in France between April 2003 and December 2008. RESULTS: The estimated mean time between infection and diagnosis ranged from 37.0 months among men who have sex with men to approximately 53.0 months among heterosexual men. Intermediate values were obtained for injecting drug users and heterosexual women. We estimated that mean times changed very slightly (≤1.2 months) during the period 2004-2007: it shortened among MSM, remained stable among non-French-national heterosexual men, and lengthened in all the other exposure categories. We estimated that the total number of new infections increased, but not significantly, between 2004 and 2007, reaching 7851 [95% confidence interval 5400-9919] in 2007. MSM accounted for the largest number of new infections (38%). CONCLUSION: HIV continues to spread in France, and the average time between infection and HIV diagnosis remains excessively long. New policies to expand the offer and acceptance of voluntary HIV testing are thus urgently needed. Our method will also be very useful to monitor and evaluate the impact of future HIV testing policies.