Lack of Evidence for Changing Virulence of HIV-1 in North America

Background: Several long-term cohort studies and in-vitro fitness assays have resulted in inconsistent reports on changes in HIV-1 virulence, including reports of decreasing, stable, and increasing virulence over the course of the AIDS pandemic. We tested the hypothesis of changing HIV-1 virulence by examining trends in prognostic clinical markers of disease progression from 1984 to 2005 among nearly 400 antiretroviral-naı¨ve participants in the United States Multicenter AIDS Cohort Study (MACS), a longitudinal study of HIV infection in men who have sex with men (MSM). \ud \ud Methodology/Principal Findings:\ud Because clinical AIDS endpoints could not be used (due to antiretroviral therapies and prophylaxis), three prognostic markers of disease progression were used as proxies for HIV-1 virulence: plasma viral RNA load and CD4+ T cell count at ‘‘set point’’ (between ~9 and ~15 months after seroconversion), and rate of CD4 cell decline within three years after seroconversion. We performed multivariate analyses of the association between these markers and seroconversion year, with covariates including MACS site, race/ethnic group, seroconversion age, and CCR5D32 status. No statistically significant association was found between year of seroconversion and ‘‘set point’’ plasma viral load (at ~9 months after seroconversion: slope =20.004 log10\ud copies/mL/year, p = 0.76; at ~15 months: slope =20.005 log10 copies/mL/year, p = 0.71), CD4 cell count after seroconversion (at ~9 months: slope =20.112 cells/mL/year, p = 0.22; at ~15 months: slope =20.047 cells/mL/year, p = 0.64), or rate of CD4 cell decline over the first three years after seroconversion (slope =20.010 cells/ul/yr2, p = 0.88). \ud \ud Conclusions/Significance: The lack of significant trends from 1984 to 2005 in these prognostic markers of HIV disease progression suggests no major change in HIV-1 virulence over the AIDS pandemic in MSM in the US

HIV-2 Integrase Variation in Integrase Inhibitor-Naïve Adults in Senegal, West Africa

Antiretroviral therapy for HIV-2 infection is hampered by intrinsic resistance to many of the drugs used to treat HIV-1. Limited studies suggest that the integrase inhibitors (INIs) raltegravir and elvitegravir have potent activity against HIV-2 in culture and in infected patients. There is a paucity of data on genotypic variation in HIV-2 integrase that might confer intrinsic or transmitted INI resistance.We PCR amplified and analyzed 122 HIV-2 integrase consensus sequences from 39 HIV-2-infected, INI-naive adults in Senegal, West Africa. We assessed genetic variation and canonical mutations known to confer INI-resistance in HIV-1.No amino acid-altering mutations were detected at sites known to be pivotal for INI resistance in HIV-1 (integrase positions 143, 148 and 155). Polymorphisms at several other HIV-1 INI resistance-associated sites were detected at positions 72, 95, 125, 154, 165, 201, 203, and 263 of the HIV-2 integrase protein.Emerging genotypic and phenotypic data suggest that HIV-2 is susceptible to the new class of HIV integrase inhibitors. We hypothesize that intrinsic HIV-2 integrase variation at "secondary" HIV-1 INI-resistance sites may affect the genetic barrier to HIV-2 INI resistance. Further studies will be needed to assess INI efficacy as part of combination antiretroviral therapy in HIV-2-infected patients

HIV-1 Superinfection in the Antiretroviral Therapy Era: Are Seroconcordant Sexual Partners at Risk?

Acquisition of more than one strain of human immunodeficiency virus type 1 (HIV-1) has been reported to occur both during and after primary infection, but the risks and repercussions of dual and superinfection are incompletely understood. In this study, we evaluated a longitudinal cohort of chronically HIV-infected men who were sexual partners to determine if individuals acquired their partners' viral strains.Our cohort of HIV-positive men consisted of 8 couples that identified themselves as long-term sexual partners. Viral sequences were isolated from each subject and analyzed using phylogenetic methods. In addition, strain-specific PCR allowed us to search for partners' viruses present at low levels. Finally, we used computational algorithms to evaluate for recombination between partners' viral strains.All couples had at least one factor associated with increased risk for acquisition of new HIV strains during the study, including detectable plasma viral load, sexually transmitted infections, and unprotected sex. One subject was dually HIV-1 infected, but neither strain corresponded to that of his partner. Three couples' sequences formed monophyletic clusters at the entry visit, with phylogenetic analysis suggesting that one member of the couple had acquired an HIV strain from his identified partner or that both had acquired it from the same source outside their partnership. The 5 remaining couples initially displayed no evidence of dual infection, using phylogenetic analysis and strain-specific PCR. However, in 1 of these couples, further analysis revealed recombinant viral strains with segments of viral genomes in one subject that may have derived from the enrolled partner. Thus, chronically HIV-1 infected individuals may become superinfected with additional HIV strains from their seroconcordant sexual partners. In some cases, HIV-1 superinfection may become apparent when recombinant viral strains are detected

HIV-1 Envelope Subregion Length Variation during Disease Progression

The V3 loop of the HIV-1 Env protein is the primary determinant of viral coreceptor usage, whereas the V1V2 loop region is thought to influence coreceptor binding and participate in shielding of neutralization-sensitive regions of the Env glycoprotein gp120 from antibody responses. The functional properties and antigenicity of V1V2 are influenced by changes in amino acid sequence, sequence length and patterns of N-linked glycosylation. However, how these polymorphisms relate to HIV pathogenesis is not fully understood. We examined 5185 HIV-1 gp120 nucleotide sequence fragments and clinical data from 154 individuals (152 were infected with HIV-1 Subtype B). Sequences were aligned, translated, manually edited and separated into V1V2, C2, V3, C3, V4, C4 and V5 subregions. V1-V5 and subregion lengths were calculated, and potential N-linked glycosylation sites (PNLGS) counted. Loop lengths and PNLGS were examined as a function of time since infection, CD4 count, viral load, and calendar year in cross-sectional and longitudinal analyses. V1V2 length and PNLGS increased significantly through chronic infection before declining in late-stage infection. In cross-sectional analyses, V1V2 length also increased by calendar year between 1984 and 2004 in subjects with early and mid-stage illness. Our observations suggest that there is little selection for loop length at the time of transmission; following infection, HIV-1 adapts to host immune responses through increased V1V2 length and/or addition of carbohydrate moieties at N-linked glycosylation sites. V1V2 shortening during early and late-stage infection may reflect ineffective host immunity. Transmission from donors with chronic illness may have caused the modest increase in V1V2 length observed during the course of the pandemic

Susceptibility of the human retrovirus XMRV to antiretroviral inhibitors

<p>Abstract</p> <p>Background</p> <p>XMRV (xenotropic murine leukemia virus-related virus) is the first known example of an exogenous gammaretrovirus that can infect humans. A limited number of reports suggest that XMRV is intrinsically resistant to many of the antiretroviral drugs used to treat HIV-1 infection, but is sensitive to a small subset of these inhibitors. In the present study, we used a novel marker transfer assay to directly compare the antiviral drug sensitivities of XMRV and HIV-1 under identical conditions in the same host cell type.</p> <p>Results</p> <p>We extend the findings of previous studies by showing that, in addition to AZT and tenofovir, XMRV and HIV-1 are equally sensitive to AZddA (3'-azido-2',3'-dideoxyadenosine), AZddG (3'-azido-2',3'-dideoxyguanosine) and adefovir. These results indicate that specific 3'-azido or acyclic nucleoside analog inhibitors of HIV-1 reverse transcriptase (RT) also block XMRV infection with comparable efficacy <it>in vitro</it>. Our data confirm that XMRV is highly resistant to the non-nucleoside RT inhibitors nevirapine and efavirenz and to inhibitors of HIV-1 protease. In addition, we show that the integrase inhibitors raltegravir and elvitegravir are active against XMRV, with EC₅₀values in the nanomolar range.</p> <p>Conclusions</p> <p>Our analysis demonstrates that XMRV exhibits a distinct pattern of nucleoside analog susceptibility that correlates with the structure of the pseudosugar moiety and that XMRV is sensitive to a broader range of antiretroviral drugs than has previously been reported. We suggest that the divergent drug sensitivity profiles of XMRV and HIV-1 are partially explained by specific amino acid differences in their respective protease, RT and integrase sequences. Our data provide a basis for choosing specific antiretroviral drugs for clinical studies in XMRV-infected patients.</p

Determinants of mortality in non-neutropenic ICU patients with candidaemia

Introduction: Candidaemia in critically-ill intensive care unit (ICU) patients is associated with high crude mortality. Determinants of mortality – particularly those amenable to potential modification – are incompletely defined. Methods: A nationwide prospective clinical and microbiological cohort study of all episodes of ICU-acquired candidaemia occurring in non-neutropenic adults was undertaken in Australian ICUs between 2001 and 2004. Multivariate Cox regression analyses were performed to determine independently significant variables associated with mortality. Results: 183 episodes of ICU-acquired candidaemia occurred in 183 patients during the study period. Of the 179 with microbiological data, Candida albicans accounted for 111 (62%) episodes and Candida glabrata, 32 (18%). Outcome data were available for 173: crude hospital mortality at 30 days was 56%. Host factors (older age, ICU admission diagnosis, mechanical ventilation and ICU admission diagnosis) and failure to receive systemic antifungal therapy were significantly associated with mortality on multivariate analysis. Among the subset who received initial fluconazole therapy (n = 93), the crude mortality was 52%. Host factors (increasing age and haemodialysis receipt), but not organism- (Candida species, fluconazole MIC), pharmacokinetic- (fluconazole dose, time to initiation), or pharmacodynamic-related parameters (fluconazole dose:MIC ratio) were associated with mortality. Process of care measures advocated in recent guidelines were implemented inconsistently: follow-up blood cultures were obtained in 68% of patients, central venous catheters removed within five days in 80% and ophthalmological examination performed in 36%. Conclusions: Crude mortality remains high in Australian ICU patients with candidaemia and is overwhelmingly related to host factors but not treatment variables (the time to initiation of antifungals or fluconazole pharmacokinetic and pharmacodynamic factors). The role and timing of early antifungal intervention in critically-ill ICU patients requires further investigation.Deborah J.E. Marriott, E. Geoffrey Playford, Sharon Chen, Monica Slavin, Quoc Nguyen, David Ellis and Tania C. Sorrell for the Australian Candidaemia Stud

Graphic loans: East Asia and beyond

The national languages of East Asia (Chinese, Japanese, Korean and Vietnamese) have made extensive use of a type of linguistic borrowing sometimes referred to as a 'graphic loan'. Such loans have no place in the conventional classification of loans based on Haugen (1950) or Weinreich (1953), and research on loan word theory and phonology generally overlooks them. The classic East Asian phenomenon is discussed and a framework is proposed to describe its mechanism. It is argued that graphic loans are more than just 'spelling pronunciations', because they are a systematic and widespread process, independent of but not inferior to phonological borrowing. The framework is then expanded to cover a range of other cases of borrowing between languages to show that graphic loans are not a uniquely East Asian phenomenon, and therefore need to be considered as a major category of loan

An HIV Epidemic Model Based on Viral Load Dynamics: Value in Assessing Empirical Trends in HIV Virulence and Community Viral Load

<div><p>Trends in HIV virulence have been monitored since the start of the AIDS pandemic, as studying HIV virulence informs our understanding of HIV epidemiology and pathogenesis. Here, we model changes in HIV virulence as a strictly evolutionary process, using <i>set point viral load</i> (SPVL) as a proxy, to make inferences about empirical SPVL trends from longitudinal HIV cohorts. We develop an agent-based epidemic model based on HIV viral load dynamics. The model contains functions for viral load and transmission, SPVL and disease progression, viral load trajectories in multiple stages of infection, and the heritability of SPVL across transmissions. We find that HIV virulence evolves to an intermediate level that balances infectiousness with longer infected lifespans, resulting in an optimal SPVL∼4.75 log₁₀ viral RNA copies/mL. Adaptive viral evolution may explain observed HIV virulence trends: our model produces SPVL trends with magnitudes that are broadly similar to empirical trends. With regard to variation among studies in empirical SPVL trends, results from our model suggest that variation may be explained by the specific epidemic context, <i>e.g.</i> the mean SPVL of the founding lineage or the age of the epidemic; or improvements in HIV screening and diagnosis that results in sampling biases. We also use our model to examine trends in community viral load, a population-level measure of HIV viral load that is thought to reflect a population's overall transmission potential. We find that community viral load evolves in association with SPVL, in the absence of prevention programs such as antiretroviral therapy, and that the mean community viral load is not necessarily a strong predictor of HIV incidence.</p></div