Forms Of HIV-1 Research Articles

Impact of the COVID-19 Pandemic on tuberculosis management in India: A Brief Overview

Chronicles suggests that emerging and re-emerging viral infections disrupting the normal lifestyle of humankind, whether in the form of HIV, Ebola, Influenza, Nepah, or the current SARS-CoV-2 pandemic. Such viral infections disrupt the healthcare system along with the prevention and control of epidemics and pandemics, resulting in an increased burden of such diseases in the post-pandemic period. Tuberculosis (TB) routine services are interfered with by severe lockdowns due to the new COVID-19 virus. This article tried to measure the long-term epidemiological effects of such interruptions on TB prevalence in high-burden countries. The participating facilities performed a comprehensive review based on modifications to the care of TB patients during the COVID-19 pandemic. Retrospectively, clinical factors and household contact information were collected from a literature survey. Researchers looked at numerous strategies over the following five years to see whether they might lessen the effects on TB incidence and death. Present comprehensive literature was collected and analyzed using suitable keywords such as "COVID-19," "Pandemics," "Tuberculosis," and "India" during the current COVID-19 pandemic to investigate the influence of COVID-19 on tuberculosis management. The present article looks at the effects of the breaks in the delivery of TB care in hospital and primary care settings. Lockdown, social isolation, measures to prevent viral transmission, and public health guidelines impacted tuberculosis care. The present study revealed that the COVID-19 pandemic has adversely affected numerous TB prevention, monitoring, and treatment programs. Still, these adverse effects are diminished by the prompt restoration of TB services and the application of particular therapies as soon as restrictions are lifted.

Influence Of HIV/AIDS Policy Implementation Factors on The Performance Of Aids Commission (KPA) In Nabire Regency

Papua Province comes first nationally with the highest number of HIV/AIDS cases in Indonesia. Meanwhile at the provincial level, Nabire Regency has the highest number of HIV and AIDS cases. The HIV epidemic in Nabire Regency is classified as a generalized epidemic with the highest prevalence of cases among women, which is said to be the highest in Papua Province. The problem of HIV / AIDS is not only a health problem, but also a social problem that needs to be addressed. This has led to the formulation of public policies in the form of HIV / AIDS prevention policies. The establishment of AIDS Commission in Nabire Regency (KPAK Nabire) is one of the government's efforts to involve the general public in helping to tackle HIV / AIDS cases in Nabire Regency. In connection with the phenomenon of the problem at hand, this study aims to analyze the influence of policy implementation factors on organizational performance.
 This study applied primary data obtained through questionnaires with a final sample of 80 respondents. Data analysis was done to describe the variables using SPSS Statistics, to evaluate the research model using the SEM (Structural Equation Modeling) technique, and to test the mediation effect using the Sobel test.
 The results showed that only resource factors, bureaucratic structure, communication and disposition of the implementors that directly and indirectly influence the performance of KPAK Nabire. Meanwhile, environmental conditions did not affect the performance of KPAK Nabire. The implementor disposition mediates the influence of the factors of policy implementation on organizational performance. The analysis results also show that disposition of the implementor is the most dominant predictor of KPAK Nabire's performance.

HIV-1 Antiretroviral Resistance in Cuba, 2009-2014.

INTRODUCTION By the end of 2017, there were more than 28,000 individuals living with HIV in Cuba, over 80% receiving antiretroviral therapy, which dramatically reduces viral replication, improves immune status and decreases risk of transmission. These results could be jeopardized by emergence of HIV-1 drug resistance. In 2009, a test for HIV-1 genotypic resistance was introduced in routine clinical practice in Cuba. OBJECTIVE Investigate antiretroviral resistance and its relation to subtype distribution in HIV-1 treatment-naïve and previously treated patients in Cuba. METHODS Resistance and HIV-1 subtype distribution were determined in 342 antiretroviral treatment-naïve patients and 584 previously treated for HIV-1 whose blood specimens were sent to the Pedro Kourí Tropical Medicine Institute during 2009-2014. Transmitted drug resistance was determined using the Calibrated Population Resistance Tool v.6. Drug resistance analysis was conducted using the algorithm Rega v9.1.0. RESULTS Prevalence of transmitted drug resistance was 11.4%, and 41% of mutated viruses exhibited dual-class resistance to nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor. Overall, 84.9% of patients had ≥1 resistance mutation, 80% had ≥1 nucleoside reverse transcriptase inhibitor mutation, 71.4% had ≥1 non-nucleoside reverse transcriptase inhibitor mutation and 31.7% had ≥1 protease inhibitor mutation. K65R and K101E mutations were significantly more frequent in subtype C, L210W in CRF19_cpx, and M47V/I in CRF BGs (20, 23, 24). Full class resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and multidrug resistance were detected in 21.2%, 32.4%, 8% and 4.1% of patients, respectively. Average percentage resistance to nucleoside reverse transcriptase inhibitor, protease inhibitor, full class resistance to nucleoside reverse transcriptase inhibitor, protease inhibitor and multidrug resistance increased in patients failing two or more regimens. Nevertheless, after 2011, a declining trend was observed in the frequency of multidrug resistance and full class resistance to nucleoside reverse transcriptase inhibitors and protease inhibitors. CONCLUSIONS Detected levels of transmitted drug resistance highlight the need for a national surveillance study in treatment-naïve patients. Resistance prevalence is high in previously treated patients but appears to be decreasing over time. The frequency of resistance mutations in recombinant forms of HIV in Cuba needs further study. KEYWORDS Antiretroviral therapy, highly active antiretroviral therapy, HIV, anti-HIV agents, drug resistance, multiple drug resistance, Cuba.

Problematics of empowerment: sex worker HIV prevention in the Pacific.

A recent overview of HIV/STI prevention programmes for sex workers in the Pacific region indicates that, despite a regional policy shift from universal to targeted interventions, Pacific Island countries currently lack core HIV/STI prevention services for sex workers. Across the region, condom distribution, peer outreach and support services for sex workers have ceased even in countries where such programmes had previously existed. This article cautions that the endorsement of empowerment projects does not negate the important role of condom access in HIV and STI prevention efforts for Pacific sex workers. While community empowerment underpins, and is essential to the sustainability of, effective interventions, it does not constitute an adequate form of HIV and STI prevention in and of itself. We contend that in the context of the Pacific Islands, timely and effective HIV prevention measures must specifically attend to the implementation of, and sustained support for, behavioural interventions such as sex-worker-specific peer education, condom and lubricant distribution, and access to appropriate sexual health services. Further, the responsibility for delivery of these should not be borne solely by fledgling sex worker organizations and communities. The evolution of targeted interventions in the Pacific and the current lack of funded condom distribution programmes highlight a more generalizable imperative within HIV prevention to ensure that behaviour change efforts are not considered to be extraneous to, or rendered redundant by, empowerment-based interventions.

Cognitive deficits persist in the combination antiretroviral era: Preliminary results from the Co-morBidity in Relation to AIDS (COBRA) collaboration London cohort

Background: HIV is a neurotropic virus that if left untreated leads to a frank dementia in a significant proportion of patients. Modern combination antiretroviral therapy (cART) has transformed HIV into a chronic disease with life expectancy approaching normal. The more severe forms of HIV associated neurocognitive dysfunction (HAND) are now rarely seen but there have been many reports of more subtle cognitive deficits occurring in up to 50% of patients in the modern era. Unfortunately many previous studies have had heterogeneous patient groups or lacked appropriate controls making extrapolation to well treated patients, common in current practice, difficult. This study set out to investigate the true prevalence of cognitive dysfunction and the mechanisms underlying it in an older group of HIV positive individuals on effect cART. Methods: To date 46 participants (33 HIV-positive patients and 13 HIV-negative controls) have been recruited into the London cohort of the COBRA observational study. All participants were aged over 50 (mean age 61 ± 7.7 years) and were predominantly male (87%). All HIV positive patients were on fully suppressive stable cART > 12 months. The two groups were well matched in terms of age, gender, sexual orientation, ethnicity and educational attainment. Subjects underwent a full cognitive battery in addition to MRI scanning with a 64-direction diffusion protocol. Mean FA (fractional anisotropy) for the major white matter tracts was calculated using a white matter skeleton created from the centre of tracts common to the group and standard atlases. Results: Poorer performance on trail making tests A and B (p = 0.007 and < 0.001 respectively), the Stroop test (p = 0.006), grooved peg board test (p = 0.004) and the Wisconsin card sort test (p = 0.002) were observed in the HIV-positive group compared to the control group. After adjusting for age the mean white matter skeleton FA was highly significantly correlated (p < 0.01) with all the abnormal cognitive tests. Significantly lower FA values were observed in 24% of the major white matter tracts of the HIV-positive group compared to controls. Conclusions: Cognitive deficits in a variety of domains persist despite full suppression of HIV replication (at least in the plasma compartment) when compared to well matched controls. The reduction in cognitive performance observed is mediated in part by decreased white matter integrity manifested as lower FA values in numerous major white matter tracts. Further analysis of other MRI modalities and lumbar puncture findings of the same cohort are awaited and these may shed light further on the pathophysiology of HAND in those on fully suppressive therapy.

The unfinished nature of rights-informed HIV- and AIDS-related education: an analysis of three school-based initiatives

Over the past 25 years, there has been growing investment in concepts of rights in the areas of HIV prevention, care and treatment, including HIV- and AIDS-related education delivered in schools. Despite this increasing commitment to the notion of rights, few efforts appear to have been made to understand the varying conceptions of rights that underpin different kinds of initiatives. Engaging with a multi-disciplinary body of literature on the issue of rights, and through a focus on three rights-informed HIV- and AIDS-related initiatives, this paper seeks to address this gap in the current literature. In so doing, it also examines a central tension within human rights discourse, namely between the construal of rights as shared and universally applicable to all human beings, while being created in and limited by the location in which they were elaborated, as well as by the language used to formulate them. More explicit engagement with the diversity of approaches made possible through a commitment to human rights may facilitate forms of HIV- and AIDS-related education that are more meaningful to young people.

English

INTRODUCTION: HIV most commonly uses CCR5 and/or CXCR4 as a co-receptor to enter its target cells. Several chemokine receptors can function as viral co-receptors, but CCR5 is likely the most physiologically important co receptor during natural infection. C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. This is the process by which T cells are attracted to specific tissue and organ targets. Most forms of HIV, the virus that causes AIDS, initially use CCR5 to enter and infect host cells. We studied the prevalence of CCR5 tropism HIV1 amongst HIV positive patients attending Mahatma Gandhi hospital Jaipur. STUDY DESIGN: This was epidemiological, cross-sectional, and non-interventional study between March and April 2014 in HIV positive patients in Jaipur. METHODS: Co-receptor tropism assay was done in total nine patients who were HIV positive attending Mahatma Gandhi Hospital Dermatology &Venereology of Mahatma Gandhi Hospital OPD in one month duration time. Total nine patients were studied, seven patients were already on ART(anti-retroviral treatment) and two patients were not taking any treatment as their CD4 count were above 500 cells/ULwith low viral load. Co-Receptor tropism assay (genetic assay) CCR5 (with the help of Emcure pharmaceuticals) was done in all of them. RESULT: Only one patient had FPR below 15 %, rest 8 patients had FPR above 15%.The study showed that the prevalence of CCR5 positivity was 88.8%, whereas CXCR4 prevalence was only 11.1%.

Molecular epidemiological study on HIV/AIDS under the follow-up program in Zhejiang province in 2009

To analyze the molecular epidemiological characteristics on HIV infectors/AIDS patients (HIV/AIDS) under a follow-up program in Zhejiang province in 2009. 303 cases were randomly sampled. Information on the cases was collected and followed by genomic DNA extraction. Gag gene fragments were amplified by nested PCR, followed by sequencing and bio-informatic analysis. The rate of success for sequence acquisition was 74.3% (225/303). Distributions of HIV subtypes were as follows: CRF01_AE (58.7%), CRF07_BC (13.8%), CRF08_BC (9.8%), B' (15.1%), C (1.8%), G (0.4%) and unassigned BC (unique recombinant form 0.4%). from the HIV BLAST analysis showed that the sources of strains with the highest homology involved in 10 provinces/municipalities (Liaoning, Guangxi, Yunnan, Henan, etc.) and five other countries (Thailand, Vietnam, India, South Africa and Libya). The CRF01_AE phylogenetic tree was divided into four clusters. The sequences of HIV/AIDS with homosexual transmission showed a gather in cluster 1, and mix with those infected through heterosexual contact. Circulating recombinant forms of HIV seemed to play a dominant role in Zhejiang province. Unique recombinant form and new subtype of HIV were found. People living with HIV under homosexual transmission and heterosexual transmission had a trend of interwoven with each other. Increase of both the diversity and complexity of HIV strains were also noticed in Zhejiang province.

A Study of Knowledge &amp; Awareness Regarding HIV / AIDS among Nursing Students

Background: HIV/AIDS can be called our modern pandemic, affecting both industrialized and developing countries. According to UNAIDS estimates, there are 33.3 million people living with HIV in which 30.8 millions are adult (15.5 millions are women) and around 2.5 millions are children. During 2009 some 2.6 million people newly infected with HIV and an estimated 1.5 million people died from AIDS. So HIV today is a threat to men, women and children of all continents. Due to frequent and prolonged contact with the patients, nursing students are being identified as a potential high risk group for the HIV/AIDS spread so keeping this thing in mind we have selected the nursing students for the study to assess their level of knowledge&awareness regarding HIV/AIDS. Research Question: What is the level of knowledge and awareness among Nursing students regarding various aspects of HIV/AIDS? Objective: To assess the level of knowledge and their awareness regarding HIV/AID Study Design: Cross Sectional Study Setting and Participants: All Nursing Students of SVS Nursing College, Mahabubnagar. Methodology: After the ethical clearance, the Present study was carried out in the last week of November 2011,with the aim to assess the status of knowledge and awareness regarding HIV/AIDS among 2nd, 3rd & final year nursing students of SVS college of nursing, Mahabubnagar A.P. For collection of data a pre designed, pre tested questionnaire were given to all the participants to fill up during the class in the lecture gallery who were present on that day. The data was collected and analyzed in descriptive statistical method. Results: Out of total 190 nursing students, 168 (88.42%) students participated in this study, in which 83% were female & 17% were male. Most of the students (96%) were in the age group of 18-24 years. The full form of HIV and AIDS were not known to 48% & 17% participants respectively. Around 83% participants said that sexual route is the most common route for HIV transmission. Around 3.58% participants were having the misconception that HIV transmission is possible through hugging, sharing toilet seats, towels, utensils, shaking hands with HIV infected patients. Most of students (95.23%) were aware regarding the various preventive measures for HIV/AIDS. Around 86.90% participants were aware that most commonly immune System is affected by HIV. Some 14.88% participants said that Vaccine is available for HIV/AIDS&15.47% said that it is curable. Around 31% participants were afraid of cross infection in giving nursing care to HIV/AIDS. Around 44.50% participants said that ART in PEP for HIV/AIDS is not useful.

The prevalence of HIV-1 DNA in AIDS-related lymphoma and Kaposi Sarcoma throughout the AIDS epidemic

Background Chronic inflammation is linked to tumorigenesis for many cancer types and likely contributes to tumor development in the HIV-infected patient population. AIDSrelated lymphoma (ARL) and Kaposi Sarcoma (KS), two AIDS-defining cancers, are associated with the tumor viruses EBV and KSHV, respectively. However, EBV is only detectable in ~40% of ARLs and KSHV alone is not sufficient for KS development. Recent studies have shown that HIV is localized to tumor associated macrophages (TAM), not malignant B cells, in a portion of EBV-negative ARLs suggesting, that HIV infected TAM may play ar ole in tumorigenesis. The goal of this research was to determine the prevalence of HIV+ ARL and KS throughout the AIDS epidemic and examine tumor associated HIV for unique genetic signatures. Material and methods Whole genomic amplified DNA from ARL and KS biopsies was used for quantitative HIV gag gene amplification. The 3’ env-LTR segment of HIV-1 genomes from tumor and non-tumor tissues from two patients that died of ARL were sequenced and Bayesian phylogenies were inferred using BEAST. All specimens were provided by the AIDS and Cancer Specimen Resource. Results Of the 119 ARL and 91 KS biopsies, 45% and 40% contained detectable HIV-1 DNA, respectively. There was a significant decrease in the prevalence of HIV-1 DNA positive ARL and KS cases in the post-HAART era (after 1996; ARL=39%, KS=16.7) as compared to preHAART (ARL=54%, KS=45%). Our data suggest the overall amount of HIV DNA is less in tumor biopsies from the post-HAART era. A subset of ARL contained extremely high levels of HIV-1 DNA (~1 copy/cell). In addition, visceral KS had a higher prevalence of HIV-1 DNA (51.9%) as compared to skin KS (30.7%). HIV sequence evolution analysis of metastatic ARLs revealed that HIV was compartmentalized within sites of lymphoma and was distinct from HIV present in nonlymphoma sites. Conclusions The prevalence of HIV-1 DNA positive ARLs declined in the post-HAART era, but not to the same extent as KS, consistent with the incidence of both tumor types in the post-HAART era. Higher prevalence of HIV-1 DNA in visceral sites of KS and lymphoma specific-HIV sequences in sites of metastatic lymphoma suggests that HIV, especially HIV infected macrophages, may play a role in the pathogenesis of KS and ARL disease progression. Additionally, HIV-infected macrophages are a source of chronic inflammation that may further enhance tumorigenesis. Our data suggest a tumor specific form of HIV may be evolving within individuals who develop ARL.

Abstract 2714: High HIV-1 DNA copy number defines a unique subset of AIDS-related lymphoma

Abstract Despite highly active antiretroviral therapy (HAART), the risk of developing non-Hodgkin lymphoma is ∼100X greater in the HIV-infected population compared to non-infected individuals and AIDS-related lymphoma (ARL) prevalence is expected to rise in the future. Preliminary reports have suggested that some ARLs contain HIV-infected macrophages that may contribute to ARL pathogenesis. A recent study evaluating HIV sequence evolution in the contest of metastatic ARL found lymphoma specific HIV compartmentalized within sites of lymphoma that was distinct from HIV present in non-lymphoma sites (Salemi et al, PLOSone Dec 3, 2009). These data suggested the existence of a lymphoma specific form of HIV evolving within individuals who develop ARL. The goal of this research was to determine the prevalence and quantity of HIV-1 DNA in 119 ARL biopsies from the entire span of the HIV epidemic (1982-2007) by utilizing whole genomic amplified (WGA) ARL DNA, provided by the AIDS and Cancer Specimen Resource (ACSR). The presence of HIV-1 DNA was determined by quantitative amplification of the HIV gag gene using single copy genes to define HIV copy numbers per genomic equivalent. Of the 119 ARL cases, 45% contained detectable levels of HIV-1 DNA (&amp;gt; 1 copy per 30,000 cells). The relationship between HIV DNA presence and tumor immunophenotype was determined using ARL data from the ACSR on the cases studied. The level of HIV per genomic equivalent in the 45% HIV DNA positive cases was as high as one/cell equivalent. There was a significant (p&amp;lt;0.01) decrease in the prevalence of HIV-1 DNA-positive ARL cases post-HAART (after 1996; 39%) as compared to pre-HAART (before 1996; 54%). Additionally, our data suggest that the overall amount of HIV-1 DNA present in ARLs was less in the post-HAART era when compared to the pre-HAART era. The HIV DNA positive cases fell into a positive outcome category (MUM1 negative and CD10 positive) based on lymphoma immunophenotype literature (p&amp;lt; 0.02). Thus, a subset of ARLs containing high levels of HIV DNA, falls into a better outcome category based on immunophenotype data and may represent a different lymphoma pathogenic process. The existence of lymphoma specific variants of HIV is currently under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2714. doi:10.1158/1538-7445.AM2011-2714

Abstract 5353: Identification of a subset of AIDS related lymphoma (ARL) containing HIV infected macrophages that is immunophenotypically distinct from EBV+ ARL

Abstract The risk of developing non-Hodgkin lymphoma is 60X greater in the HIV-infected population when compared to non-infected individuals despite the initiation of highly active antiretroviral therapy (HAART). The primary difference between lymphoma in non-infected individuals and those with AIDS related lymphoma (ARL) is that ARL is high-grade and metastatic. Since the introduction of HAART the incidence of ARL has decreased but not the same extent as other AIDS-related malignancies and there has been little change amongst the CD4 strata. Therefore, with the increase in life expectancy afforded by HAART, the overall number of ARL cases is expected to rise in the future. Preliminary reports have suggested that some ARLs contain HIV-infected macrophages that may contribute to ARL pathogenesis. A recent study evaluating HIV sequence evolution in the contest of metastatic ARL found lymphoma specific HIV compartmentalized within sites of lymphoma that was distinct from HIV present in non-lymphoma sites (Salemi et al, PLOSone Dec 3, 2009). These data suggested the existence of a lymphoma specific form of HIV evolving within individuals who develop ARL. The goal of this research was to determine the incidence of HIV infected lymphomas in the pre and post-HAART eras and if HIV-positive lymphomas have a specific immunophenotype. A tissue microarray containing ∼150 of ARLs (from 1982-2007) was obtained through the AIDS and Cancer Specimen Resource (ACSR) and was used for HIV p24 and macrophage CD68 immunohistochemistry. Double staining techniques confirmed that p24 expression was localized to tumor associated macrophages (TAM). There was a highly significant (p&amp;lt;0.001) increase in the frequency of p24+ ARL cases post-HAART (after 1996; 49%) as compared to pre-HAART (before 1996; 26%). Using antigen expression data CD20, CD3, CD10, BCL6, BCL2, MUM1, Ki67, blimp, p53 and EBV, provided by the ACSR, we were able to determine that p24+ ARLs were generally of B cell origin but did not have a specific immunophenotype. In contrast, EBV+ ARLs were more likely to express MUM1 or blimp and less likely to express CD29, CD10 or BCL6. EBV status was not associated with a pre/post HAART diagnosis (44 vs. 40%). However, a subset of EBV-/p24+ tumors was identified. In the pre-HAART era, 13% of the tumors were EBV-/p24+ compared to 30% in the post-HAART era suggesting, that the incidence of this tumor type is increasing (p&amp;lt;0.05). These data describe for the first time the existence of potentially tumor specific HIV in up to 1/3 of all post HAART ARLs, a class of tumor that is immunophenotypically distinct from EBV+ ARLs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5353.

Genetic Analysis of HIV in AIDS Malignancies

Many HIV associated diseases such as KS have resolved or dramatically decreased since the institution of HAART. Two diseases, HIV associated dementia (HAD) and AIDS related lymphoma (ARL) continue to occur and represent two diseases where HIV infected macrophages have been implicated in disease pathogenesis. In order to test whether persistent macrophage reservoirs of HIV might in part be responsible for subsets of these diseases, a survey of tissues obtained from the AIDS and Cancer Specimen Resource (ACSR) was performed. HIV copy and HIV genetic diversity studies were carried out on DNA extracted from HAD brain, ARL and KS specimens. In this pilot study, all HAD involved sections of brain, 10/14 ARL's and 1/11 KS tissues contained > 1 copy of HIV/2000 genomic equivalents. Phylodynamic analysis of the HIV in the HAD and ARL cases demonstrated the presence of dominant/monophyletic forms of compartmentalized HIV is diseased tissues. By comparison only diverse forms of HIV were observed within uninvolved tissues from the same (HAD or ARL) patient, or within KS tissues. Further genetic analysis of HIV from one patient with both HAD and primary CNS ARL, revealed distinctly different LTR's associated with the ARL as compared to the HAD. The ARL LTR was missing an NFk-B site whereas the HAD LTR carried both sites consistent with B-clade forms of HIV. These data suggest that a persistent macrophage based reservoir of HIV may contribute to ARL. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

Quantitative Structure-Activity Relationship Study of 2-arylsulfonyl-6-substituted Benzonitriles as Non-nucleoside Reverse Transcriptase Inhibitors of HIV-1

The reverse transcriptase inhibition of HIV-1, the most common form of HIV, by non-nucleoside 2-arylsulfonyl-6-substituted benzonitriles is analysed through Fujita-Ban and Hansch approaches. The analyses have helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds. From both approaches it appeared that SO 2 instead of SO or S at X; and NH 2 instead of F at Y (see Figure 1) are advantageous to improving the activity of a compound against HIV-1. This in turn leads to the suggestion that the 2-arylsulfonyl-6-aminobenzonitrile scaffold is the only appropriate structural entity that may further result into potential compounds. Further, the compounds having a OMe substituent at the ortho -position, the bulkier substituents at meta -positions and "no" substituent at para -position of 2-arylsulfonyl moiety are beneficial in raising the activity. The two quantitative structure-activity relationship (QSAR) analyses, differing in parametric approach, therefore, provided the grounds for rationalizing the substituent selection in designing more potent compounds of the series.

Trp42 rotamers report reduced flexibility when the inhibitor acetyl-pepstatin is bound to HIV-1 protease.

The Q7K/L331/L631 HIV-1 protease mutant was expressed in Escherichia coli and the effect of binding a substrate-analog inhibitor, acetyl-pepstatin, was investigated by fluorescence spectroscopy and molecular dynamics. The dimeric enzyme has four intrinsic tryptophans, located at positions 6 and 42 in each monomer. Fluorescence spectra and acrylamide quenching experiments show two differently accessible Trp populations in the apoenzyme with k(q1) = 6.85 x 10(9) M(-1) s(-1) and k(q2) = 1.88 x 10(9) M(-1) s(-1), that merge into one in the complex with k(q) = 1.78 x 10(9) M(-1) s(-1). 500 ps trajectory analysis of Trp X1/X2 rotameric interconversions suggest a model to account for the observed Trp fluorescence. In the simulations, Trp6/Trp6B rotameric interconversions do not occur on this timescale for both HIV forms. In the apoenzyme simulations, however, both Trp42s and Trp42Bs are flipping between X1/X2 states; in the complexed form, no such interconverions occur. A detailed investigation of the local Trp environments sampled during the molecular dynamics simulation suggests that one of the apoenzyme Trp42B rotameric interconversions would allow indole-quencher contact, such as with nearby Tyr59. This could account for the short lifetime component. The model thus interprets the experimental data on the basis of the conformational fluctuations of Trp42s alone. It suggests that the rotameric interconversions of these Trps, located relatively far from the active site and at the very start of the flap region, becomes restrained when the apoenzyme binds the inhibitor. The model is thus consistent with associating components of the fluorescence decay in HIV-1 protease to ground state conformational heterogeneity.

An African HIV-1 sequence from 1959 and implications for the origin of the epidemic.

There is considerable genetic diversity among viruses of different subtypes (designated A to J) in the major group of human immunodeficiency virus type 1 (HIV-1), the form of HIV that is dominant in the global epidemic. If available, HIV-1 sequences pre-dating the recognition of AIDS could be crucial in defining the time of origin and the subsequent evolution of these viruses in humans. The oldest known case of HIV-1 infection was reported to be that of a sailor from Manchester who died of an AIDS-like illness in 1959; however, the authenticity of this case has not been confirmed. Genetic analysis of sequences from clinical materials obtained from 1971 to 1976 from members of a Norwegian family infected earlier than 1971 showed that they carried viruses of the HIV-1 outlier group, a variant form that is mainly restricted to West Africa. Here we report the amplification and characterization of viral sequences from a 1959 African plasma sample that was previously found to be HIV-1 seropositive. Multiple phylogenetic analyses not only authenticate this case as the oldest known HIV-1 infection, but also place its viral sequence near the ancestral node of subtypes B and D in the major group, indicating that these HIV-1 subtypes, and perhaps all major-group viruses, may have evolved from a single introduction into the African population not long before 1959.

HIV-induced cytopathology and viral load in a pentamidine-treated lymphocytic cell line

Preincubation of CD4 lymphocytes with pentamidine isethionate at a concentration of 1.5 mg/L then removal from incubation medium prior to addition of HIV-1, or incubation of cells with the drug and virus simultaneously, increased HIV-1 DNA load but reduced p24 antigen release. The number of syncytia generated was not affected by the presence of pentamidine. The extent of balloon degeneration of cells was greater, however, although this was not associated with a discernable increase in cellular necrosis or reduction in cell viability. This suggests that drug-treatment resulted in an increased load of intracytoplasmic (but not necessarily integrated) forms of HIV- 1; this may explain the lower levels of antigen produced and also the balloon degeneration of treated cells, a phenomenon previously observed with other retroviruses.

Identification of a Clonal Form of HIV in Early Kaposi??s Sarcoma

We recently reported clonal human immunodeficiency virus (HIV involvement in four acquired immune deficiency syndrome (AIDS)-associated non-B-cell lymphoproliferations. In three of these cases HIV expression was localized to tumor-associated macrophages. Because one of the cases had a major component involved in angioproliferation, we speculated that some form of Kaposi's sarcoma (KS), which also has a major component of angioproliferation, might be involved clonally with HIV. The current study is an evaluation of four cases of KS and control tissues taken from four patients who died with complications of HIV disease. With use of the inverse polymerase chain reaction technique to identify clonal forms of HIV, a clonal form of HIV was found in one of four KS cases. The HIV-positive tumor was an early KS lesion of the bowel, and uninvolved bowel from the same patient showed no clonal HIV. Immunohistochemical analysis demonstrated the presence of prominent HIV-expressing macrophages that also coexpressed high levels of HIV tat, basic fibroblast growth factor, and interleukin-6. These data provide evidence for a pathogenic process termed "sequential neoplasia," wherein a clonal macrophage provides a growth factor milieu stimulating the proliferation of a responder cell population that ultimately becomes autonomous. In the current case, the macrophages expressing HIV were located adjacent to the KS tumor tissue and were found to be producing known KS growth factors. The absence of finding clonal HIV in three more advanced KS lesions suggests that the clonal macrophage may be required only for early pathogenesis and that sequential neoplastic changes occurring in the endothelial cells gave rise to autonomous KS.(ABSTRACT TRUNCATED AT 250 WORDS)