Novitsky V, Ndung’u T, Wang R, Bussmann H, Chonco F, Makhema J, et al. Extended high viremics: a substantial fraction of individuals maintain high plasma viral RNA levels after acute HIV-1 subtype C infection
Harvard School of Public Health, Boston, Massachusetts 02115, USA. AIDS (London, England)
(Impact Factor: 5.55).
04/2011; 25(12):1515-22. DOI: 10.1097/QAD.0b013e3283471eb2
The present study addressed two questions: what fraction of individuals maintain a sustained high HIV-1 RNA load after the acute HIV-1C infection peak and how long is a high HIV-1 RNA load maintained after acute HIV-1C infection in this subpopulation?
Plasma HIV-1 RNA dynamics were studied in 77 participants with primary HIV-1C infection from African cohorts in Gaborone, Botswana, and Durban, South Africa. HIV-infected individuals who maintained mean viral load of at least 100,000 (5.0 log(10)) copies/ml after 100 days postseroconversion (p/s) were termed extended high viremics. Individuals were followed longitudinally for a median [interquartile range (IQR)] of 573 (226-986) days p/s.
The proportion of extended high viremics was 34% [95% confidence interval (CI) 23-44%] during the period 100-300 days p/s and 19% (95% CI 9-29%) over the period of 200-400 days p/s. The median (IQR) duration of HIV-1 RNA load at least 100,000 copies/ml among extended high viremics was 271 (188-340) days p/s. For the subset with average viral load at least 100,000 copies/ml during 200-400 days p/s, the median (IQR) duration was 318 (282-459) days. The extended high viremics had a significantly shorter time to CD4 cell decline to 350 cells/μl (median: 88 vs. 691 days p/s for those not designated as extended high viremics; P < 0.0001, Gehan-Wilcoxon test).
A high proportion of extended high viremics - individuals maintaining high plasma HIV-1 RNA load after acute infection - have been identified during primary HIV-1 subtype C infection. These extended high viremics likely contribute disproportionately to HIV-1 incidence.
Available from: Laith J Abu-Raddad
- "Different circulating virus sub-types are another potential biological cofactor. HIV-1 subtype C is found predominantly in areas of high HIV prevalence in SSA and appears to be linked to extended high viremia (Kaul et al., 2011; Novitsky et al., 2011). Other potential biological cofactors include STIs such as herpes simplex virus type 2 (Abu-Raddad et al., 2008; Korenromp et al., 2001), tropical co-infections increasing HIV viral load (Abu-Raddad et al., 2006, 2013), hormonal contraception (Heffron et al., 2012), and host genetics and immunology (Kaul et al., 2011). "
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Representative and precise estimates for the annual risk of HIV transmission (ϕ) from the infected to the uninfected partner in a stable HIV-1 sero-discordant couple (SDC) are not available. Nevertheless, quantifying HIV infectiousness is critical to understanding HIV epidemiology and implementing prevention programs.
Materials and methods
We estimated ϕ and examined its variation across 23 countries in sub-Saharan Africa (SSA) by constructing and analyzing a mathematical model that describes HIV dynamics among SDCs. The model was parameterized using empirical measures such as those of the nationally representative Demographic and Health Surveys. Uncertainty and sensitivity analyses were conducted to assess the robustness of the findings.
We estimated a median ϕ of 11.1 per 100 person-years across SSA. A clustering based on HIV population prevalence was observed with a median ϕ of 7.5 per 100 person-years in low HIV prevalence countries (<5%) compared to 19.5 per 100 person-years in high prevalence countries (>5%). The association with HIV prevalence explained 67% of the variation in ϕ, and suggested an increase of 0.95 per 100 person-years in ϕ for every 1% increase in HIV prevalence.
Empirical measures from cohort studies appear to underestimate HIV infectiousness in SSA. The risk of HIV transmission among SDCs appears also to vary across SSA, and this may have contributed to the contrasting HIV epidemic trajectories in this continent.
Available from: Guinevere Q. Lee
- "Indeed, it has been proposed that lower replication capacity but equal (or perhaps enhanced) transmissibility of subtype C isolates favor their ability to spread, and thus contribute to their higher global prevalence [21,24,49]. Although inter-subtype differences in HIV-1 pathogenicity or rate of disease progression remain controversial [21-23,50-54], it is conceivable that the diversity in Nef functions observed in this study could contribute to inherent differences in the intra- and inter-subtype pathogenicity of globally diverse HIV-1 strains. "
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ABSTRACT: The highly genetically diverse HIV-1 group M subtypes may differ in their biological properties. Nef is an important mediator of viral pathogenicity; however, to date, a comprehensive inter-subtype comparison of Nef in vitro function has not been undertaken. Here, we investigate two of Nef's most well-characterized activities, CD4 and HLA class I downregulation, for clones obtained from 360 chronic patients infected with HIV-1 subtypes A, B, C or D.
Single HIV-1 plasma RNA Nef clones were obtained from N=360 antiretroviral-naive, chronically infected patients from Africa and North America: 96 (subtype A), 93 (B), 85 (C), and 86 (D). Nef clones were expressed by transfection in an immortalized CD4+ T-cell line. CD4 and HLA class I surface levels were assessed by flow cytometry. Nef expression was verified by Western blot. Subset analyses and multivariable linear regression were used to adjust for differences in age, sex and clinical parameters between cohorts. Consensus HIV-1 subtype B and C Nef sequences were synthesized and functionally assessed. Exploratory sequence analyses were performed to identify potential genotypic correlates of Nef function. Subtype B Nef clones displayed marginally greater CD4 downregulation activity (p = 0.03) and markedly greater HLA class I downregulation activity (p < 0.0001) than clones from other subtypes. Subtype C Nefs displayed the lowest in vitro functionality. Inter-subtype differences in HLA class I downregulation remained statistically significant after controlling for differences in age, sex, and clinical parameters (p < 0.0001). The synthesized consensus subtype B Nef showed higher activities compared to consensus C Nef, which was most pronounced in cells expressing lower protein levels. Nef clones exhibited substantial inter-subtype diversity: cohort consensus residues differed at 25% of codons, while a similar proportion of codons exhibited substantial inter-subtype differences in major variant frequency. These amino acids, along with others identified in intra-subtype analyses, represent candidates for mediating inter-subtype differences in Nef function.
Results support a functional hierarchy of subtype B > A/D > C for Nef-mediated CD4 and HLA class I downregulation. The mechanisms underlying these differences and their relevance to HIV-1 pathogenicity merit further investigation.
Available from: John J Potterat
- "Rather, we hypothesize that a combination of sexual mixing in a high-prevalence setting, structural factors that put young people at increased risk of exposure and unique biological factors, such as the predominance of clade C HIV  , is driving the epidemic in sub- Saharan Africa over and above individual sexual behaviors. Kenyon et al assert that we dismiss the role of behavior, in particular concurrency, and also race in explaining differences in the epidemics observed in South Africa and the United States. "
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