Autocatalytic maturation, physical/chemical properties and crystal structure of group N HIV-1 Protease: Relevance to drug resistance.

Protein Sci. 2010 Aug 24;

Authors: Sayer JM, Agniswamy J, Weber IT, Louis JM

The mature protease from group N HIV-1 (PR1(N)) differs in 20 amino acids from the extensively studied group M protease (PR1(M)) at positions corresponding to minor drug-resistance mutations (DRMs). The first crystal structure (1.09 A resolution) of PR1(N) with the clinical inhibitor darunavir (DRV) reveals the same overall structure as PR1(M), but with a slightly larger inhibitor binding cavity. Changes in the 10's loop and the flap hinge propagate to shift one flap away from the inhibitor, while L89F and substitutions in the 60's loop perturb inhibitor-binding residues 29-32. However, kinetic parameters of PR1(N) closely resemble those of PR1(M), and calorimetric results are consistent with similar binding affinities for DRV and two other clinical PIs, suggesting that minor DRMs co-evolve to compensate for the detrimental effects of drug-specific major DRMs. A miniprecursor (TFR(1-61)-PR1(N)) comprising the transframe region (TFR) fused to the N-terminus of PR1(N) undergoes autocatalytic cleavage at the TFR/PR1(N) site concomitant with the appearance of catalytic activity characteristic of the dimeric, mature enzyme. This cleavage is inhibited at an equimolar ratio of precursor to DRV ( approximately 6 muM), which partially stabilizes the precursor dimer from a monomer. However, cleavage at L34/W35 within the TFR, which precedes the TFR(1-61)/PR1(N) cleavage at pH </= 5, is only partially inhibited. Favorable properties of PR1(N) relative to PR1(M) include its suitability for column fractionation by size under native conditions and >10-fold higher dimer dissociation constant (150 nM). Exploiting these properties may facilitate testing of potential dimerization inhibitors that perturb early precursor processing steps.

PMID: 20737578 [PubMed - as supplied by publisher]

Astrocytes contacting HIV-1-infected macrophages increase the release of CCL2 in response to the HIV-1-dependent enhancement of membrane-associated TNFalpha in macrophages.

Glia. 2010 Aug 24;

Authors: Muratori C, Mangino G, Affabris E, Federico M

The presence of human immunodeficiency virus (HIV)-infected macrophages in the parenchyma of central nervous system is an hallmark of acquired immunodeficiency syndrome-related neuroinflammation. Once penetrated the blood-brain barrier (BBB), macrophages closely interact with astrocytes, beginning with those lying beneath the BBB endothelium. By investigating the consequences of the cell-cell interaction between HIV-infected macrophages and astrocytes, we observed that the HIV-1 expression in macrophagic cells correlated with increased chemotactic activity in supernatants of astroglial cells. Gene array analysis revealed an impressive increase in the transcription of the gene for the CCL2/MCP-1 chemokine in astroglial cells isolated from HIV-1-infected co-cultures compared with cells from uninfected co-cultures. This phenomenon coupled with the increase in CCL2 release and depended on the cell-cell contact. In addition, it was a consequence of the HIV-1-induced enhancement of membrane-associated tumor necrosis factor-alpha in macrophagic cells, and correlated with increased levels of nuclear factor kappaB activation in astroglial cells. These observations could mirror a mechanism of recruitment of leukocytes through the BBB, likely contributing to the increase in both viral load and inflammation in central nervous system of HIV-infected patients. (c) 2010 Wiley-Liss, Inc.

PMID: 20737475 [PubMed - as supplied by publisher]

Intravaginal insertion in KwaZulu-Natal: sexual practices and preferences in the context of microbicide gel use.

Cult Health Sex. 2010 Aug 23;:1

Authors: Gafos M, Mzimela M, Sukazi S, Pool R, Montgomery C, Elford J

Intravaginal insertion is often associated with the concept of 'dry' sex. All HIV-prevention microbicides tested to date have been vaginally applied lubricant-based gels. In this paper, we examine whether the use of intravaginal insertions could be in conflict with the introduction of vaginal microbicide gels. The Africa Centre site was part of the Microbicides Development Programme evaluating PRO2000/5 microbicide gel. We conducted in-depth-interviews and focus-group discussions with women enrolled in the trial as well as women and men from the community. The analysis focused on people's knowledge of intravaginal insertion in the community and trial participants' experience of using trial gels. Intravaginal use of a variety of products was widely acknowledged. We found that the experience of using trial gels - which made sex 'hot', 'tight' and 'dry' - matched the desired outcomes of intravaginal insertion. We found that vaginal 'dryness' described the removal of excessive amounts of unusual discharge, rather than the removal of normal vaginal secretions and that intravaginal insertion is not exclusively associated with a desire for 'dry' sex. Study findings provide evidence that vaginal microbicide gels may be more acceptable in communities where intravaginal insertion is practiced than was previously thought.

PMID: 20737330 [PubMed - as supplied by publisher]

The use of cell-delivered gene therapy for the treatment of HIV/AIDS.

Immunol Res. 2010 Aug 25;

Authors: Symonds GP, Johnstone HA, Millington ML, Boyd MP, Burke BP, Breton LR

HIV/AIDS is a disease that impairs immune function, primarily by decreasing T-lymphocyte count. Its progression can be contained by highly active antiretroviral therapy (HAART), but there are side effects that can be severe, and the development of resistance often forces the physician to modify the HAART regimen. There are no vaccines available for HIV. An alternative approach that could provide a path to a curative therapy is the use of cell-delivered gene therapy in which an anti-HIV gene(s) is introduced into hematopoietic cells to produce a population that is protected from the effects of HIV. In this paper, we review the field and discuss an approach using a short hairpin RNA to CCR5, an important co-receptor for HIV.

PMID: 20737298 [PubMed - as supplied by publisher]

Increasing and Supporting the Participation of Persons of Color Living with HIV/AIDS in AIDS Clinical Trials.

Curr HIV/AIDS Rep. 2010 Aug 25;

Authors: Gwadz MV, Colon P, Ritchie AS, Leonard NR, Cleland CM, Riedel M, Bowens D, Banfield AD, Chang P, Quiles R, Mildvan D

Persons living with HIV/AIDS (PLHA) of color are under-represented in AIDS clinical trials (ACTs), which may limit the generalizability of research findings and denies many individuals access to high levels of care and new treatments available through ACTs. Disproportionately low rates of recruitment in health care settings and by providers are a major barrier to ACTs for this group. Moreover, PLHA of color are more likely than their white peers to decline to participate, mainly due to fear and mistrust (although willingness is also high), negative social norms about ACTs, and difficulty navigating the unfamiliar ACT system. We describe a small number of successful behavioral and structural interventions to increase the participation of PLHA of color in screening for and enrollment into ACTs. HIV care settings, clinical trials sites, and trial sponsors are uniquely positioned to develop procedures, supports, and trials to increase the proportion of PLHA of color in ACTs.

PMID: 20737252 [PubMed - as supplied by publisher]

Factors influencing the quality of life in patients with HIV in Malaysia.

Qual Life Res. 2010 Aug 26;

Authors: Hasanah CI, Zaliha AR, Mahiran M

PURPOSE: The aim of this study was to determine the socio-demographic, clinical and psychological factors influencing the quality of life (QOL) in patients with human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS). METHODS: This was a cross-sectional study on 271 patients with HIV infection attending an HIV clinic in Kota Bharu, Malaysia. Participants completed the Malay version of the Functional Assessment of HIV Infection (FAHI) and Malay Hospital Anxiety Depression Scale (HADS). RESULTS: The patients functioned satisfactorily in the physical domain. They were mostly impaired in the social domain. Those who acquired the HIV infection via a heterosexual route seemed to have a significantly lower social well-being, while those who acquired HIV via drug injection were not associated with losses in the overall QOL or any of its domains. Non-disclosure paradoxically had a greater effect on social well-being. About 38% had possible anxiety, depression or both, and these emotional disturbances were significantly associated with total FAHI and its five domains. CONCLUSIONS: Psychological and social well-beings were more affected than physical well-being in out-patients with HIV infection in Kota Bharu, Malaysia. The study suggests that the patients with HIV infection should receive better psycho-education and psychological intervention.

PMID: 20737215 [PubMed - as supplied by publisher]

[Isospora belli infection in HIV positive patients: report of two cases and literature review]

Rev Chilena Infectol. 2010 Jun;27(3):219-27

Authors: Neira O P, Barthel M E, Wilson L G, Muñoz S N

Isosporosis is an infection caused by parasitic protozoa of the genus Isospora, coccidia affecting various different vertebrate species, including humans. It is an uncommon infection in our country and it is not a zoonosis. We present two cases of Isospora belli infection in HIV positive patients from the Valparaiso region. We discuss the clinical events caused by this agent, its epidemiology, cases published in the local and foreign literature, as well as its treatment and prevention measures.

PMID: 20737124 [PubMed - in process]

[Guidelines on HIV/AIDS]

Rev Chilena Infectol. 2010 Jun;27(3):197-8

Authors: Afani S A, Pérez C C, Vásquez T P, Wolff R M

PMID: 20737118 [PubMed - in process]

Pulmonary Infections and Risk of Lung Cancer Among Persons With AIDS.

J Acquir Immune Defic Syndr. 2010 Aug 23;

Authors: Shebl FM, Engels EA, Goedert JJ, Chaturvedi AK

Lung cancer risk is significantly increased among persons with AIDS (PWA), and increased smoking may not explain all of the elevated risk, suggesting a role for additional cofactors. We investigated whether AIDS-defining pulmonary infections (recurrent pneumonia, Pneumocystis jirovecii pneumonia, and pulmonary tuberculosis) affected the risk of subsequent lung cancer over 10 years after AIDS onset among 322,675 PWA, whose records were linked with cancer registries in 11 US regions. We assessed lung cancer hazard ratios (HRs) using Cox regression and indirectly adjusted HRs for confounding by smoking. Individuals with recurrent pneumonia (n = 5317) were at significantly higher lung cancer risk than those without [HR = 1.63, 95% confidence interval (CI) = 1.08 to 2.46, adjusted for age, race, sex, HIV acquisition mode, CD4 count, and AIDS diagnosis year]. This association was especially strong among young PWA (<50 years HR = 1.99 vs. >/=50 years HR = 1.10) and was significantly elevated during 5-10 years after recurrent pneumonia diagnosis (HR = 2.41; 95% CI = 1.07 to 5.47). Although attenuated, HRs for recurrent pneumonia remained nonsignificantly elevated after indirect adjustment for smoking. Lung cancer risk was unrelated to tuberculosis [(n = 13,878) HR = 1.12, 95% CI = 0.82 to 1.53] or Pneumocystis jirovecii pneumonia [(n = 69,771) HR = 0.97, 95% CI = 0.80 to 1.18]. The increased lung cancer risk associated with recurrent pneumonia supports the hypothesis that chronic pulmonary inflammation arising from infections contributes to lung carcinogenesis.

PMID: 20736841 [PubMed - as supplied by publisher]

Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load.

AIDS. 2010 Aug 25;

Authors: Cu-Uvin S, Delong AK, Venkatesh KK, Hogan JW, Ingersoll J, Kurpewski J, De Pasquale MP, Dʼaquila R, Caliendo AM

OBJECTIVE:: Few studies have assessed longitudinal genital tract HIV-1 shedding. We determined patterns of genital tract HIV-1 RNA shedding over time among women with suppressed plasma viral load (PVL) on antiretroviral treatment. METHODS:: Paired plasma and genital tract HIV-1 RNA were measured every 4 weeks. Participants were classified as persistent, intermittent, or nonshedders. Longitudinal analysis examined rates of genital tract shedding and the association with PVL, CD4 cell count, and genital tract infections. Markov transition models were used to describe the dynamics of HIV-1 RNA in plasma and genital tract using visit-to-visit transitions from and to detectable and undetectable PVL or genital tract HIV-1 RNA. RESULTS:: Fifty-nine women contributed 582 study visits of whom 95 and 98% had below-detectable PVL and genital tract viral load, respectively, at baseline. Thirty-two of 59 women (54%) had detectable HIV-1 RNA at least once in the genital tract. Twenty-two of 59 (37%) women had detectable genital tract HIV-1 RNA during a study visit when PVL was undetectable; 6.8% of the women were persistent shedders, 31% were intermittent shedders, and 45.8% were nonshedders. Sampling three subcompartments increased detection of HIV-1 genital tract viral load compared to sampling a single subcompartment. Overall, genital tract HIV-1 RNA shedding in any subcompartment occurred at about 13% of visits. Shedding in at least one of the three subcompartments occurred at 9% of visits when PVL was undetectable (95% confidence interval 6-14%). CONCLUSION:: Women with below-detectable PVL may have less risk of HIV sexual transmission on a population level, but may continue to be infectious on an individual level.

PMID: 20736815 [PubMed - as supplied by publisher]

Population-based V3 genotypic tropism assay: a retrospective analysis using screening samples from the A4001029 and MOTIVATE studies.

AIDS. 2010 Aug 25;

Authors: McGovern RA, Thielen A, Mo T, Dong W, Woods CK, Chapman D, Lewis M, James I, Heera J, Valdez H, Harrigan PR

BACKGROUND:: The MOTIVATE-1 and 2 studies compared maraviroc (MVC) along with optimized background therapy (OBT) vs. placebo along with OBT in treatment-experienced patients screened as having R5-HIV (original Monogram Trofile). A subset screened with non-R5 HIV were treated with MVC or placebo along with OBT in a sister safety trial, A4001029. This analysis retrospectively examined the performance of population-based sequence analysis of HIV-1 env V3-loop to predict coreceptor tropism. METHODS:: Triplicate V3-loop sequences were generated using stored screening plasma samples and data was processed using custom software ('ReCall'), blinded to clinical response. Tropism was inferred using geno2pheno ('g2p'; 5% false positive rate). Primary outcomes were viral load changes after starting maraviroc; and concordance with prior screening Trofile results. RESULTS:: Genotype and Trofile results were available for 1164 individuals with virological outcome data (N = 169 non-R5 by Trofile). Compared with Trofile, V3 genotyping had a specificity of 92.6% and a sensitivity of 67.4% for detecting non-R5 virus. However, when compared with clinical outcome, virological responses were consistently similar between Trofile and V3 genotype at weeks 8 and 24 following the initiation of therapy for patients categorized as R5. CONCLUSION:: Despite differences in sensitivity for predicting non-R5 HIV, week 8 and 24 week virological responses were similar in this treatment-experienced population. These findings suggest the potential utility of V3 genotyping as an accessible assay to select patients who may benefit from maraviroc treatment. Optimization of the predictive tropism algorithm may lead to further improvement in the clinical utility of HIV genotypic tropism assays.

PMID: 20736814 [PubMed - as supplied by publisher]

Darunavir concentrations exceed the protein-corrected EC50 for wild-type HIV in the semen of HIV-1-infected men.

AIDS. 2010 Aug 31;

Authors: Taylor S, Jayasuriya AN, Berry A, Gilleran G, Dufty NE, Else L, Back DJ, Smit EJ

Variable antiretroviral drug penetration into the genital tract may contribute to the differential evolution of HIV-1 and the emergence of drug resistance. We compared concentrations of darunavir in 34 time-matched blood plasma and seminal plasma samples from 18 HIV-1 positive men. Darunavir in seminal plasma were approximately 10-20% of that achieved in blood at matched time points postdrug ingestion. All seminal plasma darunavir were above the protein-corrected EC50 values for wild-type HIV-1.

PMID: 20736813 [PubMed - as supplied by publisher]

How much do they know about sexual health?: Knowledge and information-seeking behaviors of Spanish-speaking immigrant adolescents in Curacao, Netherlands Antilles.

Fam Community Health. 2010 Oct-Dec;33(4):285-300

Authors: Hammer J, Rao SP, Banegas MP

Scant HIV/AIDS prevalence data from Curacao suggest that 65.9% of the HIV/AIDS cases in the Netherlands Antilles are currently being documented in this country. The present cross-sectional qualitative study evaluated levels of knowledge of sexual health and information-seeking behavior of Spanish-speaking immigrant adolescents in Curacao. Findings point to a greater need for channels of sexual health information targeting adolescents that focus on the interpersonal aspects of sexuality, to encourage greater parental involvement in their adolescents' lives, and to improve communications between adolescents and their parents. Study findings also suggest the need for a more thoughtful and systematic exploration of the indications by participants that force/coercion specifically by older men including stepfathers was a reason for sexual initiation of many young Latina girls in Curacao.

PMID: 20736756 [PubMed - in process]

Nontyphoidal salmonellosis in Africa.

Curr Opin Infect Dis. 2010 Oct;23(5):409-14

Authors: Graham SM

PURPOSE OF REVIEW: This review aims to identify and highlight important data published in the past 12 months which provide new information on nontyphoidal salmonellosis in Africa. RECENT FINDINGS: Recent reviews and clinical studies continue to emphasize the challenges of diagnosis and management of invasive nontyphoidal Salmonellae (NTS) disease as a major cause of mortality in African children and HIV-infected African adults. New observational evidence of the association between malaria and NTS disease in African children has been published. An improved understanding of disease pathogenesis has been provided with evidence of persistent intracellular infection in HIV-infected adults. Multidrug resistance of NTS is now widespread in the region. A novel variant of NTS has emerged which is now a common cause of invasive disease in African populations, and it shows evidence of adaptation to human host and has acquired virulence plasmids along with multidrug resistance. Recent studies have provided original data of the importance of humoral immunity in African children, which informs the development of vaccine. SUMMARY: NTS are a major cause of invasive disease in Africa. Recent studies provide a range of helpful insights and novel data which could inform strategies for improving management and especially prevention of this neglected disease.

PMID: 20736739 [PubMed - in process]

Ethics and the standards of prevention in HIV prevention trials.

AIDS. 2010 Sep 10;24(14):2298-9; author reply 2299-300

Authors: Sugarman J, Grace WC

PMID: 20736687 [PubMed - in process]