AIDS: is there an answer to the global pandemic? The immune system in HIV infection and control.
ABSTRACT HIV/AIDS continues to spread globally and remains a worldwide pandemic affecting about 40 million people. The prevention of infection remains paramount to vaccine studies. Although the best immune correlates for an efficacious HIV vaccine have not yet been discovered, progress has been made toward developing a vaccine. The identification of an effective antibody-binding site, targeted by a functional neutralizing antibody, and findings confirming that the Gag-specific responses are effective in protecting against disease progression are major advances in this field. This review highlights immunology-based developments in vaccine research and viral and host cell properties that could be employed to curb the spread of HIV.
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ABSTRACT: Existing antiretroviral treatments for HIV type-1 (HIV-1) disease are limited by problems of resistance and drug-drug interactions. Bevirimat is a novel HIV-1 maturation inhibitor with a mechanism of action that is distinct from other antiretroviral agents. Specific inhibition of the final rate-limiting step in Gag processing by bevirimat prevents release of mature capsid protein from its precursor (CA-SP1), resulting in the production of immature, non-infectious virus particles. Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients, with peak plasma concentrations attained approximately 1-3 h after dosing. Plasma concentrations decrease in a log-linear manner with a mean plasma elimination halflife of 58-80 h, supporting once-daily dosing. Animal studies suggest that elimination of bevirimat is primarily by hepatic glucuronidation and hepatobiliary excretion. There is minimal renal elimination, with < 1% of the administered dose appearing in the urine. In responsive patients, bevirimat has demonstrated a robust dosedependent reduction in viral load (> 1.5 log10 copies/ml). Short-term administration (< or = 14 days) of bevirimat is well tolerated, even when used in combination with other antiretroviral agents. Further studies to evaluate the long-term efficacy and tolerability of bevirimat are currently underway.Antiviral chemistry & chemotherapy 02/2008; 19(3):107-13. DOI:10.1177/095632020801900301
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ABSTRACT: Cell surface receptors, such as the CCR5 chemokine receptors, represent key determinants of the human immunodeficiency virus type 1 (HIV-1) entry into target cells. The CC-chemokine, RANTES (regulated upon activation, normal T-cell expressed and secreted), a ligand for CCR5, have been targeted to the lumen of endocytoplasmic reticulum (ER) using a KDEL (ER-retention signal) fusion termed RANTES-KDEL and this construct was found to prevent effectively transport of newly synthesized CCR5 to the cell surface. Lentiviral vectors have emerged as potent and versatile tools of gene transfer for basic and applied research are able to transduce nondividing cells and maintain sustained long-term expression of transgenes. For this reason, an HIV-based lentiviral vector expressing RANTES-KDEL, pLenti6/V5-R-K, was constructed and then cotransfected with the ViraPower Packaging Mix (pLP1, pLP2, and pLP/VSVG) into 293FT cells to produce a replication-incompetent lentivirus stock. The lentiviral stock was titrated using HeLa cells, and the expression of the gene of interest, RANTES, was detected by indirect immunofluorescence. Based on the above results, the lentiviral stock was transduced into CD34(+) human hematopoietic stem cells (hHSC) separated magnetically from the cord blood (the purity was 96.8% evaluated by flow cytometry). Finally, the levels of p24 in the cultures of pLenti6/V5-R-K-transduced CD34(+) hHSC were detected after infection by HIV-1 DP1 (a R5-tropic HIV-1 strain, which was isolated by the Centers for Disease Control and Prevention of China in Henan province in 2000 from a Chinese man who had asymptomatic HIV-1 infection with a history of blood transfusions). It was shown that pLenti6/V5-R-K transduction inhibited expression of the DP1 p24 antigen by 51%, 58% and 60% on the 4th, 7th and 10th day respectively (P<0.05).Journal of Virological Methods 08/2008; 154(1-2):194-9. DOI:10.1016/j.jviromet.2008.07.003 · 1.78 Impact Factor
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ABSTRACT: Background: Most HIV-seropositive people who develop AIDS die from an opportunistic infection, such as pulmonary mycosis, rather than the HIV infection itself. Data on the pattern of respiratory mycoses and the immunological profile of HIV-seropositive patients in Nigeria are scarce and uncoordinated, so we investigated respiratory mycosis and CD4 count among HIV-seropositive and AIDS patients attending the antiretroviral clinics at the University of Calabar Teaching Hospital and Lawrence Henshaw Hospital in Calabar, Nigeria. Method: From May 2009 to July 2010 we carried out a prospective study of 331 individuals with respiratory symptoms, of whom 272 were HIV seropositive, aged 17-75 years and able to produce sputum and 59 were HIV non-reactive. Relevant samples were collected and subjected to direct microscopy, fungal culture and serology. Results: The overall prevalence of pulmonary mycoses was 36.0%, the most prevalent fungal pathogen being Candida albicans (11.8%). Pneumocystis jirovecii (7.4%) was confirmed as an important opportunistic fungal agent in HIV-infected individuals in Calabar. Patients aged 25-34 years were at the highest risk of pulmonary mycosis (43.9%). HIV-positive patients with mycoses had lower mean CD4 counts (142.3 ± 100.1 cells µl⁻¹) than those without mycoses (435.4 ± 249.1 cells µl⁻¹) (t = 10.5, p = 0.00). Conclusion: Opportunistic pulmonary infections arise more frequently in HIV patients with lower CD4 counts. A more detailed comparative study with other opportunistic infections may help formalize the use of CD4 count as an indicator of HIV/AIDS with opportunistic mycoses.Transactions of the Royal Society of Tropical Medicine and Hygiene 01/2013; 107(3). DOI:10.1093/trstmh/trs025 · 1.84 Impact Factor