Current HIV Research (v.9, #1)

A RhoA-Derived Peptide Inhibits Human Immunodeficiency Virus-1 Entry In Vitro by Maciej Maselko, Casey Ward, Manoj Pastey (1-5).
RhoA-derived peptides have been shown to have antiviral activity against both human respiratory syncytial virus and human parainfluenza virus-3. The present study investigates the toxicity, anti-HIV-1 activity and mechanism of action of a RhoA-derived peptide (RhoA 77-95). The efficacy of this peptide was compared to a scrambled peptide of the same amino acid composition and Enfuvirtide, a HIV entry inhibitor. Our data show that this RhoA-derived peptide is a non-toxic and effective inhibitor of a CXCR4 tropic strain of HIV-1. We also demonstrate that the mechanism of entry inhibition is likely mediated by polyanionic properties and is dependent on the dimerization of peptides.

Chronic immune activation driven by microbial translocation from a damaged gut plays a fundamental role in HIV-1 progression. However, the exact link between a leaky gut and immune activation remains to be established. A growing body of evidence suggests that high mobility group box protein-1 (HMGB1) may be involved in this process. HMGB1 is a DNA binding protein present in every nucleated cell, which might be actively secreted to the extracellular milieu by activated cells or passively released from damaged or dying cells. The biological effect depends on its ability to form complexes: HMGB1 alone signals through the receptor of advanced glycosylated end products (RAGE) and promotes regeneration and repair, whereas HMGB1 in complex with bacterial products signal via toll like receptors (TLRs) and promotes immune activation. Plasma levels of HMGB1 are elevated in HIV-1 infected patients and reduced by antiretroviral therapy. The protein might be released from necrotic and apoptotic HIV-1 infected cells. HMGB1 may stimulate or inhibit HIV-1 replication in vitro, depending on the stage of infection, type of cell and purity of the protein: The protein has been suggested to reduce viral replication by interfering with viral entry in acute infection and to increase viral replication in latently infected cells. Finally, HMGB1 in combination with microbial products/TLR ligands seems to be associated with increased viral replication in vitro and in vivo.

HIV Infection Induces Morphometrical Changes on the Oral (Buccal Mucosa and Tongue) Epithelial Cells by Adriane Bastos Pompermayer, Francisca Berenice Dias Gil, Beatriz Helena Sottile Franca, Maria Angela Naval Machado, Paula Cristina Trevilatto, Angela Fernandes, Antonio Adilson Soares de Lima (11-16).
The aim of this study was to assess morphological and morphometrical alterations of oral squamous epithelial cells in type 1 HIV infected individuals. Oral smears were collected from tongue and buccal mucosa of 30 HIV infected (experimental) and 30 non-infected (control) individuals by liquid-based exfoliative cytology. The cells were morphologically analyzed and the nuclear area (NA), the cytoplasmic area (CA) and the nucleus-to-cytoplasm area ratio (NA/CA) were calculated. No morphological differences were found between the groups. The mean values of CA were decreased in tongue (P.00006) and buccal mucosa (P=.00242) in HIV infected individual, while mean values of NA were increased (P=.00308 and .00095, respectively) in the same group. NA/CA ratio for experimental group was increased in both collected places, with P=.00001 (tongue) and P=.00000 (buccal mucosa). This study revealed that HIV infection was able to induce morphometrical changes on the oral epithelial cells.

Accumulation of Defective HIV-1 Variants in a Patient with Slow Disease Progression by Stefania Paolucci, Roberto Gulminetti, Renato Maserati, Luca Dossena, Fausto Baldanti (17-22).
Viral population in a long term non progressor carrying CRF02-AG HIV-1 virus variants with a truncated RT gene and attenuated virus replication was analyzed. The proportion of mutant and wild-type RT sequences was determined by clonal analysis of HIV-1 DNA and RNA from blood samples and peripheral blood mononuclear cell (PBMC) culture supernatants. Recombinant HIV-1 strains were generated by reverse genetics to evaluate the replicative capacity of RT variants in PBMC cultures. HIV-1 RNA and DNA sequences in PBMC cultures showed a mixture of stop codons (RTSTOP), recombinant forms, (RTRF), and full length (RTFL) strains. In plasma, proportion of HIV-1 RNA sequences with a truncated RT gene fluctuated over time (0and#x25; in 2005, 100and#x25; in 2007 and 8.3and#x25; in 2010), while in proviral DNA was constant (96.5and#x25; to 100and#x25;). Reconstituted RTSTOP strains were unable to replicate in PBMC. However, RTFL strains could trans-complement the loss of function of RTSTOP variants. In vivo selection of stop codons in the RT gene resulted in the accumulation of replication-defective virus strains. Nevertheless, the observed release of defective viral particles in plasma was probably the result of viral protein complementation between replication-competent and replication-incompetent HIV-1 variants. The divergence in the proportion of RTSTOP and RTFL variants as well as in the mutation's pattern to antiretroviral drug resistance between HIV- 1 plasma RNA and PBMC proviral DNA, suggested that circulating lymphocytes expressing full-length RT might be negatively selected for by a specific T-cell response, possibly contributing to the slow progression to AIDS observed in this patient.

Aminotransferase Serum Levels Decrease after Initiating Antiretroviral Treatment in HIV Infected Patients by Jose Antonio Mata-Marin, Jesus Gaytan Martinez, Rafael Arias Flores, Sergio Mendoza Alvarez, Ivan de Jesus Asencio Montiel (23-27).
Aim: To evaluate the effect of antiretroviral treatment on aminotransferase serum levels in treatment-naive patients infected with human immunodeficiency virus (HIV). Methods: We conducted a longitudinal study in treatment-naive patients infected with HIV. Patients were excluded if they had consumed alcohol during the last three months or had an opportunistic disease or co-infection. All 54 enrolled patients were evaluated and those having a CD4+ cell count andlt; 350 cells/ml (41/54) were allocated to the treatment group (TG), while those with CD4+ counts > 350 cells/ml (13/54) did not receive any anti-retroviral treatment (ART). TG patients received either efavirenz (EFV) (21/41) or lopinavir/ritonavir (LPV/RTV) (20/41), each with zidovudine/lamivudine (ZDV/LMV). Results: During the trial, 2 subjects in the EFV group were excluded due to rash and 1 subject in the LPV/RTV group due to gastric intolerance. The remaining 51 subjects (13 (25.5and#x25;) in the NTG and 38 (74.5and#x25;) in the TG) were included in the data analysis. Overall, 43 (84and#x25;) of analyzed patients were male and 8 (16and#x25;) female with an overall mean age of 33 and#xB1; 9 years. Of the 38 treated patients, 19 received LPV/RTV and 19 received EFV. Patients in the TG showed an increase in their CD4+ cell count, a decrease in aspartate aminotransferase (AST) from 39.3 and#xB1; 28 IU/ml to 22.7 and#xB1; 6 IU/ml (p = 0.02), and a decrease in alanine aminotransferase (ALT) from 52.0 and#xB1; 25 IU/ml to 23.8 and#xB1; 13 IU/ml (p andlt; 0.01). Patients in the NTG showed no statistically significant differences in these measurements. Positive correlation was found between HIV viral load, AST (r = 0.31, p = 0.001) and ALT (r = 0.40, p = 0.04). Conclusions: There is a significant decrease in aminotransferase serum levels following the initiation of antiretroviral treatment in HIV infected patients.

Retroperitoneal Cryptococcoma in a Case of Disseminated Cryptococcosis on Antifungal Maintenance Therapy by Giovanna Ferraioli, Caterina Cavanna, Manjula Ricciardi, Silvio Daffara, Laura Sangiovanni, Carlo Filice, Giorgio Barbarini (28-30).
Cryptococcoma is a rare entity, characterized by solid, space-occupying masses, usually found in the brain. It has been reported in the setting of and#x201C;paradoxicaland#x201D; immune reconstitution inflammatory syndrome. A case of retroperitoneal cryptococcoma in a HIV-infected woman with a clinical history of disseminated cryptococcosis on antifungal maintenance therapy is described.

Fat Tissue Distribution Changes in HIV-Infected Patients Treated with Lopinavir/Ritonavir. Results of the MONARK Trial by Sami Kolta, Philippe Flandre, Philippe Ngo Van, Isabelle Cohen-Codar, Marc-Antoine Valantin, Claire Pintado, Philippe Morlat, Francois Boue, Richard Rode, Michael Norton, Brygida Knysz, Karine Briot, Christian Roux, Jean-Francois Delfraissy (31-39).
Given the decline in mortality among HIV-infected patients, it has become increasingly important to consider delayed disease-related and/or anti-HIV therapy-related adverse effects, such as lipodystrophy, when choosing initial therapy. Data from the MONARK trial allowed for comparison of the potential lipodystrophic effects of lopinavir/ritonavir (LPV/r) monotherapy with those of triple therapy with LPV/r plus zidovudine (ZDV) and lamivudine (3TC). This was a randomized, open-label, multinational study that included 136 antiretroviral-naive HIV-infected patients. A portion of study patients underwent evaluations of limb and trunk fat tissue by dual-energy x-ray absorptiometry at baseline and after 48 weeks of treatment (and 96 weeks in some patients). Sixty-three patients had paired absorptiometry data at baseline and week 48 (13 patients at week 96). At week 48, median change in limb fat was - 63 g on LPV/r monotherapy versus -703 g on LPV/r + ZDV/3TC triple therapy (p=0.014). The proportion of patients with fat loss ( > 20and#x25; loss in limb fat) was significantly lower with LPV/r monotherapy (4.9and#x25; versus 27.3and#x25;; p=0.018). Changes in trunk fat did not differ significantly between treatments. Nonetheless, limb fat and trunk fat varied in the same direction with both treatments. The decrease in arm lean mass was also significantly less in patients receiving LPV/r monotherapy. Only treatment type emerged as a significant predictor of fat loss (odds ratio, 7.06; 95and#x25; CI, 1.11-78.69). These results suggest that LPV/r, and possibly other protease inhibitors, may not be the main contributor to lipoatrophy in HIV-infected patients receiving triple therapy.

Long-Term Safety from the Raltegravir Clinical Development Program by Hedy Teppler, Deborah D. Brown, Randi Y. Leavitt, Peter Sklar, Hong Wan, Xia Xu, Fabio Lievano, Heidi P. Lehman, T. Christopher Mast, Bach-Yen T. Nguyen (40-53).
Background: Raltegravir has demonstrated potent and durable efficacy and a favorable safety profile in 3 phase III studies in treatment-naive and treatment-experienced patients with HIV-1 infection. This manuscript provides a review of the raltegravir safety profile using data from these and other studies in the clinical development program. Methods: Comprehensive 96-week safety data from STARTMRK (raltegravir versus efavirenz, each with tenofovir/emtricitabine) and BENCHMRK (raltegravir versus placebo, each with optimized background therapy) are summarized. A cumulative meta-analysis of raltegravir 400 mg bid was conducted across the entire development program. Results: In STARTMRK, drug-related adverse events (AEs) occurred less frequently with raltegravir than efavirenz. In BENCHMRK, the most common drug-related AEs occurred at generally similar frequencies in both groups. Drug-related serious AEs were uncommon. Rash was observed in raltegravir-treated patients at a higher frequency than placebo but a lower frequency than efavirenz. Depression and immune reconstitution inflammatory syndrome occurred at similar rates for raltegravir and comparators. Isolated elevations of creatine kinase were more common with raltegravir than placebo but occurred without clinical manifestations. The frequency of aminotransferase elevations was greater in patients with viral hepatitis co-infection, but similar in the raltegravir and comparator groups. The relative risk (95and#x25; CI) of cancer was 0.75 (0.30, 1.91) indicating no difference between raltegravir and comparator. Overall trends in the cumulative metaanalysis were similar to those observed in the phase III studies. Conclusions: Long-term data from the phase III clinical trials demonstrate that raltegravir was generally well-tolerated in both treatment-naive and treatment-experienced patients with HIV infection.

Late and Low Compliance with Hepatitis B Serology Screening Among HIV-Infected Patients in a Resource-Limited Setting: An Issue to Improve HIV Care by Sasisopin Kiertiburanakul, Darunee Chotiprasitsakul, Kalayanee Atamasirikul, Somnuek Sungkanuparph (54-60).
Although hepatitis B serology screening has been recommended for HIV care, it has not been routinely performed. We aimed to assess compliance and timing of hepatitis B serology screening among HIV-infected patients in a resource-limited setting. A cross-sectional study was conducted in Thailand. Compliance, timing of hepatitis B serology screening, and factors associated with no HBsAg screening were determined. A total of 416 HIV-infected patients with 61and#x25; males were enrolled. Median (range) age at HIV diagnosis was 34 (16-75) years and 92and#x25; had heterosexual risk. Proportion of HBsAg screening and prevalence of positive HBsAg were 69.2and#x25; and 9.0and#x25;, respectively. There was no difference in the proportion of no HBsAg screening during the period 1990-2008 (p = 0.865). Proportion of anti-HBs and anti-HBc screening were 40.9and#x25; and 21.2and#x25;, respectively. HBsAg was screened before or on the day of anti-HIV testing in 9.1and#x25; and before antiretroviral therapy (ART) initiation in 27.2and#x25;. By Kaplan-Meier analysis, median time from anti-HIV testing to HBsAg screening was 55.9 (95and#x25; confidence interval [CI] 43.9, 68.3) months. By multivariate logistic regression, duration of HIV infection (odds ratio [OR] 1.14; 95and#x25; CI 1.07, 1.21), no anti-HBs screening (OR 1.65; 95and#x25; CI 1.4-2.63), and no anti-HCV screening (OR 2.60; 95and#x25; CI 1.62, 4.17) were associated with no HBsAg screening before ART initiation. In conclusion, compliance with hepatitis B serology screening was relatively low and late. Educational program regarding hepatitis B serology screening, identification of barriers, and interventions to eliminate these barriers in resource-limited settings are crucial to improve HIV care.

Cryptogenic Liver Diseases: Sailing by Sight from HIV Co-Infection with Hepatitis Viruses to HIV Mono-Infection Through the Pillars of Hercules by Daria Gotti, Emanuele Foca, Laura Albini, Monia Mendeni, Andrea Vavassori, Eugenia Quiros Roldan, Carlo Torti (61-69).
Liver injury in the HIV-positive population has been classically associated with hepatitis B or C viruses (HBV and HCV). While HBV or HCV co-infections have represented and#x201C;Pillars of Herculesand#x201D; for hepatic disease (not further beyond), it is now time to move forward and shed light on liver disease in HIV-infected patients without HBV or HCV co-infections. Indeed, over the last years, liver disease in HIV-mono-infected patients has emerged and fated to become one of the main non AIDS-related complications. Although several cases have specific etiologies (e.g., alcohol abuse), other cases are most challenging for the clinicians because the actual causes are only hypothesized, such as it is difficult to treat them appropriately. This new clinical entity has been named and#x201C;cryptogenicand#x201D; liver disease; it is polymorphic (e.g., hepatic steatosis, nodular regenerative hyperplasia or noncirrhotic portal hypertension) and multifactorial in nature, but HIV per se may play a key role. In this paper, we present a critical review of the relevant literature data, focusing on practical implications (including diagnostic tools and differential diagnosis), and delineate priorities for future research on this important topic.