Current HIV Research (v.10, #8)

Partial Protection of SHIV-Infected Chinese Rhesus Macaques Against Super-Infection with Heterologous SHIV Isolate by Yue Li, Qiang Liu, Zhenwu Luo, Yanmeng Feng, Zhe Li, Qiang Wei, Yiming Shao (627-635).
Background: Many studies have revealed a protective effect of infection with simian immunodeficiency virus(SIV) or simian-human immunodeficiency virus (SHIV) against subsequent infection by a related immunodeficiencyvirus. However, whether a protective response can be induced by an infection with an immunodeficiency virus is stillcurrently debated in the HIV-1 vaccine field. The aim of this study was to evaluate the protection against SHIV challengein Chinese macaques that had been inoculated with SHIVs containing different HIV-1 envelops.

Methods: Eleven adult Chinese rhesus monkeys were inoculated with SHIV-KB9, SHIV-1157ipd3N4 or SHIV-CN97001.After 30 weeks, the animals were exposed to SHIV-KB9 or SHIV-CN97001, which carried a heterologous envelopeprotein relative to the first challenge strain. Infection was monitored by measuring viral load and antibody response, aswell as viral genome sequence analyses.

Results: After first challenge, all the monkeys demonstrated high viral loads and specific antibody responses. Protectionfrom super-infection was statistically significant in all the animals inoculated with SHIV-KB9 or SHIV-1157ipd3N4.However, animals inoculated with SHIV-CN97001 and challenged with SHIV-KB9 showed new infections. Thesusceptibility to super-infection was not correlated with neutralizing antibodies present at the time of exposure to thesecond virus.

Conclusions: These findings indicate that different SHIV infection may confer different levels of protection against asecond SHIV infection in Chinese monkeys. Understanding this protective response in SHIV infected macaques may sheda new light on HIV-1 vaccine development.

HIV gp120 is an Aberrant Chemoattractant for Blood Resting CD4 T Cells by Jia Guo, Xuehua Xu, Wen Yuan, Tian Jin, Yuntao Wu (636-642).
Binding of HIV gp120 to the chemokine coreceptor CXCR4 mediates signal transduction that promotes actindynamics critical for the establishment of viral latency in resting CD4 T cells. To some extent, this gp120-mediated signaltransduction resembles the chemotactic response mediated by chemokines such as the stromal cell-derived factor-1 alpha(SDF-1). It has been suggested that gp120 functions as a bona fide chemokine to attract or repel blood CD4 T cells. Todetermine whether gp120 is a viral chemoattractant, we compared the chemotactic properties of gp120 with those of SDF-1, and confirmed previous observations that gp120 possesses some chemotactic ability at certain dosages. However, whenwe examined gp120 in a range of dosages, we found that in general, gp120 only attracts or repels blood resting CD4 Tcells at a low level, and there is no clear pattern of dosage-dependency as normally seen in a typical chemokine. Theseirregularities of gp120 were observed in multiple donors. Nevertheless, gp120 aberrantly interferes with SDF-1-mediatedT cell chemotaxis and cell migration. These results suggest that gp120 does not act like a typical chemoattractant,although it triggers actin dynamics to facilitate HIV infection.

Gold Nanoparticles as an HIV Entry Inhibitor by S. Vijayakumar, S. Ganesan (643-646).
Gold nanoparticles stabilized with polyethylene glycol were used to study their cytotoxicity and antiviralactivity against HIV-1 in the laboratory. The HeLa-CD4-LTR-B-gal cell line was used with gold nanoparticles todetermine the cell viability using luminescent assay. The 50% cytotoxicity concentration, IC50 of gold nanoparticles wasfound to be 1.12 ± 0.05 mg/ml. M-tropic, T-tropic, dual tropic and resistant isolates were inhibited by gold nanoparticlesand their inhibition concentration ranged from 0.05 to 0.12 mg/ml. The mechanism of gold nanoparticles against HIV-1 isnot clear but it inhibits the HIV-1 fusion. In this study, the gold nanoparticles were used to analyze their mode of antiviralactivity and the experimental results showed that they inhibit the viral entry by binding with gp120 and prevent CD4attachment. These properties of gold nanoparticles make them as an effective antiviral inhibitor.

Resistance-Associated Mutations after Initial Antiretroviral Treatment Failure in a Large Cohort of Patients Infected with HIV-1 Subtype CRF01_AE by Jutarat Praparattanapan, Wilai Kotarathitithum, Romanee Chaiwarith, Nontakan Nuntachit, Thira Sirisanthana, Khuanchai Supparatpinyo (647-652).
The nucleoside reverse transcriptase inhibitors (NRTIs), zidovudine (AZT) and stavudine (d4T) are thymidineanalog drugs recommended as first-line antiretroviral therapy in HIV-1-naive patients. Two thymidine analog mutation(TAM) pathways, TAM-1 and TAM-2, confer high levels of resistance with mutations in the viral RT. The relativeprevalence of TAM pathways and their associations with other NRTI resistance mutations acquired under the pressure ofdrug treatment in a large cohort of 1,876 patients infected with HIV-1 CRF01_AE attending the Infectious DiseaseClinic, Chiang Mai University Hospital, Chiang Mai, Thailand, were studied. From 117 patients infected with HIV-1CRF01_AE who had plasma HIV-1 RNA of ≥500 copies/mL, 69 patients had at least one TAM. The most commonmutation associated with NRTI resistance was M184V/I (89.9%). The TAM-2 (89.9%) pathway occurred approximatelytwo times more frequently than the TAM-1 (43.5%) pathway. The presence of TAM and the TAM-1 pathway wassignificantly more frequent in the AZT- than the d4T-receiving group ((OR, 2.89; 95% CI, 1.12-7.46; P<0.05) and (OR,3.33; 95% CI, 1.19-9.37; P<0.05), respectively). In conclusion, the TAM-2 pathway was selected more frequently thanthe TAM-1 pathway by thymidine analog drugs in HIV-1 CRF01_AE-infected patients, while the TAM-1 pathwayoccurred more frequently than the TAM-2 pathway in such patients with AZT-based treatment. Routine monitoring ofplasma HIV-1 RNA may result in less exposure to failing regimens and reduce the opportunity for TAMs to accumulate.However, the low frequency of the TAM-1 pathway in our cohort data suggests that these patients should respond well tosecond-line regimens containing a ritonavir-boosted protease inhibitor.

Correlation of CYP2B6-516G>T Polymorphism with Plasma Efavirenz Concentration and Depression in HIV-Infected Adults in Northern Thailand by Linda Aurpibul, Nuntisa Chotirosniramit, Patcharaphan Sugandhavesa, Natthapol Kosashunhanan, Sunida Thetket, Taweewat Supindham, Weerawit Piyamongkol, Khuanchai Supparatpinyo (653-660).
Background: Single nucleotide polymorphism of the hepatic cytochrome P450 isoenzyme 2B6 (CYP2B6) geneis a cause of variation in plasma efavirenz (EFV) concentrations. We aimed to determine the allelic distribution ofCYP2B6 gene, plasma levels of EFV, the prevalence of clinical depression, and their correlations in northern Thaipopulation.

Methods: This was a cross-sectional study of HIV-infected patients on EFV-containing antiretroviral regimens for ≥48weeks. A single blood specimen was collected for determination of the mid-dose plasma EFV concentration and CYP2B6-516G>T polymorphism. The presence and severity of depression were assessed.

Results: One hundred patients were enrolled [mean age (± SD) was 41.81 ± 8.44 years, mean CD4 lymphocyte count 462± 193 cells/ul]. The genotype CYP2B6-516 guanine/guanine (G/G), guanine/thymidine (G/T), and T/T were found in49%, 37%, and 14% of patients, respectively. The allele frequency of CYP2B6-516 G to T replacement was 32.5%. Themedian plasma EFV concentration was 2,616 ng/mL (IQR 1,851-3,742); 79% had EFV plasma concentrations from 1,000to 4,000 ng/mL. The mean EFV concentrations for those with G/G, G/T and T/T genotypes were 2,082±630, 3,166±1,074,and 11,196±6,265 ng/mL, respectively (p<0.01). CYP2B6-516G>T polymorphism was the only factor associated withhigh plasma EFV levels. Nineteen patients had depression; 13 of 18 (72%) with mild and one with major depression hadnormal plasma EFV level. A weak correlation between plasma EFV concentrations and depression scores was observed(p=0.009, R2=0.059).

Conclusions: The prevalence of CYP2B6-516G>T polymorphism in northern Thai population is high and stronglyassociated with inter-individual drug levels variation.

Despite the remarkable success of combination antiretroviral therapy, usually including the association of threeantiretroviral drugs selected from two different classes, the possibility of treating HIV-infected patients with one singlepotent agent as simplified maintenance regimen has attracted clinicians and researchers over the past years. Monotherapywith one ritonavir-boosted protease inhibitor in subjects with persistently suppressed plasma HIV RNA offers severalpotential advantages, such as avoiding the long-term toxicity associated with nucleoside/nucleotide analog, reducingcosts, preventing drug-drug interactions, and preserving future treatment options. Several controlled and uncontrolledstudies have assessed efficacy and safety of this monotherapy strategy, and the majority of available data concernlopinavir/ritonavir and darunavir/ritonavir. The virological efficacy of these boosted protease inhibitors as monotherapy isslightly lower than that of standard therapy, but the risk of resistance development is minimal and the re-introduction ofnucleoside analogues usually leads to a re-suppression of the plasma viral load. Even though currently there is noconsensus about the clinical use of protease inhibitor monotherapy for the treatment of HIV infection, this strategy seemsan option for selected patients on stable combination therapy, with persistently suppressed plasma viral load, and withouta history of virologic failure while receiving protease inhibitors. The aim of this article is to review and summarize themost recent randomized and observational studies which have evaluated efficacy and safety of the protease inhibitormonotherapy.

Switching to Raltegravir in Virologically Suppressed in HIV-1-Infected Patients: A Retrospective, Multicenter, Descriptive Study by Daniel Podzamczer, Esteban Martinez, Pere Domingo, Elena Ferrer, Pompeyo Viciana, Jordi Curto, Maria-Jesus Perez-Elias, Antonio Ocampo, Ignacio Santos, Hernando Knobel, Vicente Estrada, Eugenia Negredo, Ferran Segura, Joaquin Portilla, Esteban Ribera, Josefa Galindo, Antonio Antela, Jorge Carmena, Manuel Castano, The TORAL Study Group (673-678).
Objectives: To describe the efficacy and tolerability of switching to raltegravir (RAL) in virologicallysuppressed HIV-1-infected patients during routine clinical practice.

Methods: A total number of 263 subjects (189 men, median age 48.1 years) with HIV-1 RNA < 50 copies/mL for ≥ 6months were switched to RAL (400 mg b.i.d). Reasons for change were toxicity (49.0%), drug interactions (6.1%) orconvenience (28.6%) (switch from subcutaneous to oral treatment 22.4%, improvement of posology 3.4%). Patients werefollowed up to 24 months after switching to RAL. Primary end-points were tolerability and virological failure defined astwo consecutive measures of HIV-1 RNA > 50 copies/mL.

Results: After a median of 12.4 months (range 2.8-26.4 months), virological failure was observed in 6 (2.3%) patients (2.2per 100 person-years [95%CI 0.9-4.6]), while AIDS occurred in 1, drug discontinuation in 4, 3 patients died and 10 werelost to follow-up. The median CD4+ T cell count increased from 460 cells/mm3 to 508.6 cells/mm3 (P < 0.001).

Conclusions: Switching to RAL in clinical practice was mainly driven by toxicity, convenience or interactions, they werewell tolerated and secured virologic suppression in the vast majority of patients.

The Effect of Unsuccessful Treatment with Peginterferon and Ribavirin on the Liver Fibrosis Course of HIV/HCV-Coinfected Patients by Julio Collazos, Victor Asensi, Belen de la Fuente, Jose-Antonio Carton (679-687).
Background: The course over time of different fibrosis parameters in HIV/HCV-coinfected patients who didnot suppress HCV during anti-HCV therapy, and in patients who suppressed HCV but relapsed after treatmentdiscontinuation is unclear.

Methods: A total of 248 patients were included in the study (81 non-responders, 49 relapsers, and 118 control, untreatedpatients). Four primary non-invasive fibrosis indices (transient elastometry, APRI, Forns, and FIB4), as well as otherfibrosis parameters, were evaluated in each group at baseline, at the end of anti-HCV therapy and at the end of follow-up(median 39.35 months from baseline).

Results: Groups were comparable in baseline characteristics, except for lower fibrosis indices in the control group. In thisgroup there was a consistent increase in all fibrosis indices over time. On the contrary, treated patients experienced certainimprovements in these indices during the period of treatment and a further worsening when the treatment was stopped, toreach the pretreatment values at the end of follow-up. Relapsers had also more favorable course than non-responders ineach fibrosis parameter, but the differences were small and not statistically significant.

Conclusions: HIV/HCV-coinfected patients who undergo unsuccessful anti-HCV treatment experience someimprovement in liver fibrosis as compared to untreated patients, although the differences are small. Relapsers have also amore favorable fibrosis course than non-responders, but the differences are minimal. These improvements are only limitedto the treatment period. Therefore the effect of unsuccessful treatment would only represent a transitory delay in fibrosisprogression.

A Cross-Sectional Epidemiological Study of Chronic HCV Liver Disease Stage in HIV-Coinfected Patients Using Noninvasive Techniques. CoTrans- GEENI Study by R. Ramirez, S. Valero, C. Escrich, J. Cucurull, A. Tapiz, E. Pedrol, the Cotrans-GEENI Study Group (688-693).
Background & Aims: Considering the disadvantages of liver biopsy, alternative noninvasive methods have beensought to assess the stage of liver fibrosis. The aim of this study is to determine the prevalence of different stages ofchronic liver disease using noninvasive methods (transition elastography (Fibroscan®) and Forns and AST-to-plateletratio index-APRI-indexes) in HCV/HIV-coinfected patients.

Materials & Methods: An observational, cross-sectional, multicenter study conducted between September 2007 and May2008. The study enrolled coinfected patients who had a transient elastography performed in the year of the study and/orbiochemical markers (Forns/APRI indexes) to assess the stage of liver fibrosis.

Results: A total of 109 patients were finally enrolled. Mean elastography velocity was 15.3 kPa, and mean APRI andForns indexes were 1.4 and 6.1, respectively. According to transient elastography: 41% had mild, 24% moderate, and 35%severe fibrosis; 35% with significant fibrosis. According to the APRI index: 29% had mild, 45% moderate, and 26%severe fibrosis; 28% with significant fibrosis. According to the Forns index: 16% had mild, 54% moderate, and 30%severe fibrosis; 30% with significant fibrosis. The Kappa concordance index between the three methods was 0.42 forfibrosis stage and 0.52 for significant fibrosis detection (p<0.001 in both cases).

Conclusions: There is concordance between the APRI and Forns indexes and elastography in the detection of differentfibrosis stages and it is significant. Transient elastography agrees with these indexes in the detection of significant andsevere fibrosis.

Motor Neuron Disease and Acquired Axonal Neuropathy Association in HIV Infection: Case Report and Update by Marco Orsini, Marcos R.G. de Freitas, Julio G. Silva, Marzia P. Sohler, Carlos H.M. Reis, Antonio M. da Silva Catharino, Acary B. Oliveira, Sergio Machado, Antonio E. Nardi, Peter Salem, Flavio Sztajnbok, Marco A.A. Leite, Cristiane Nascimento, Eduardo Davidovich, Fabio H. de Gobbi Porto, Marcia W. Cruz, Sara L.S. de Menezes, Oscar Arias-Carrion (694-699).
Background: A possible viral etiology has been documented in the genesis of motor neuron disorders andacquired peripheral neuropathies, mainly due to the vulnerability of peripheral nerves and the anterior horn to certainviruses. In recent years, several reports show association of HIV infection with Amyotrophic Lateral Sclerosis -Syndrome, Motor Neuron Diseases and peripheral neuropathies.

Objective: To report a case of an association between Motor Neuron Disease and Acquired Axonal neuropathy in HIVinfection, and describe the findings of neurological examination, cerebrospinal fluid, neuroimaging and electrophysiology.

Methods: The patient underwent neurological examination. General medical examinations were performed, including,specific neuromuscular tests, analysis of cerebrospinal fluid, muscle biopsy and imaging studies.

Results and Discussion: The initial clinical presentation of our case was marked by cramps and fasciculations withposterior distal paresis and atrophy in the left arm. We found electromyography tracings with deficits in the anterior hornof the spinal cord and peripheral nerves. Dysphagia and release of primitive reflexes were also identified. At the sametime, the patient was informed to be HIV positive with high viral load. He received antiretroviral therapy, with loadcontrol but with no clinical remission.

Conclusion: Motor Neuron disorders and peripheral neuropathy may occur in association with HIV infection. However, acausal relationship remains uncertain. It is noteworthy that the antiretroviral regimen may be implicated in some cases.

Human T-Cell Lymphotropic Virus in Patients Infected with HIV-1: Molecular Epidemiology and Risk Factors for Transmission in Piaui, Northeastern Brazil by Evaldo H. de Oliveira, Aldemir B. Oliveira-Filho, Lucinda A. Souza, Letiano V. da Silva, Marluisa O.G. Ishak, Ricardo Ishak, Antonio C.R. Vallinoto (700-707).
This study aimed to describe the epidemiological, immunological and molecular features of infection by thehuman T-lymphotropic virus-1/2 (HTLV-1/2) in individuals with HIV-1 in an urban area of Piaui State, Brazil. Exclusioncriteria included patients under 18 years of age, pregnant women or Amerindians. Of 805 individuals analyzed by theserological method (ELISA) for the detection of anti-HTLV-1/2, 18 (2.24%) were positive, but only 13 (1.61%) wereconfirmed by PCR. The RFLP analysis revealed that nine (1.12%) of these subjects were positive for HTLV-1 and four(0.5%) for HTLV-2. The mean age of these co-infected individuals was 50.9±9.1 years, and a significant association wasfound with age (above 40 years: p = 0.002), minor surgeries (p = 0.004) and blood transfusion (p = 0.031). Quantificationof the T CD4+/CD8+ lymphocytes and the HIV-1 viral load showed no significant association of T CD8 + lymphocytelevels with co-infection in the patients with HIV-1/HTLV-1. The sequencing of the LTR region and phylogenetic analysisindicated that the nine HTLV-1 strains belong to the Transcontinental subgroup of the Cosmopolitan group (1a), with a83% (neighbor-joining) bootstrap value. The HTLV-2 strains were identified as subtype HTLV-2c, supported by abootstrap value of 79%. Further studies in other population subgroups, such as blood donors and drug users, will benecessary to clarify the dissemination of HTLV-1/2 in Piaui and elucidate the developmental profile of the virus in theregion.

Monitoring Drug Use Among HIV/AIDS Patients in Brazil: Should we Combine Self-Report and Urinalysis? by Andre Malbergier, Ricardo A. do Amaral, Luciana R.D. Cardoso, Saulo Castel (708-712).
Illicit drug use in HIV-infected patients can be linked to impairment of physical and mental health, low healthrelatedquality of life, and suboptimal adherence to HIV treatment. This study aimed to evaluate the correlation of selfreportillicit drug use, urinalysis for cocaine and cannabis metabolites, and severity of dependence among HIV-infectedpatients on antiretroviral therapy (ART) in a treatment center in Brazil. Four hundred and thirty-eight outpatients of anHIV referral center were interviewed and assessed for drug use (lifetime, last year and last month). Urinalysis wasperformed to detect the presence of cocaine and cannabis metabolites in urine samples. Overall agreement between selfreportand urinalysis was almost 68% for cannabis and higher than 85% for cocaine. Positive urinalysis was significantlyassociated with more than once a week cannabis (p < .0001) and cocaine (p < .0001) use during the last-month. Severityof Dependence Scale (SDS) properly predicted positive cocaine urinalysis results (area under the curve [AUC] = .81, p =.0001). Frequency of cannabis and cocaine use, SDS score degree and positive urinalysis for both drugs were correlated.Our findings suggest that positive self-report is a reliable predictor of positive urine sample both for cannabis and cocaine,but since the agreement was not perfect, there is a role for urine drug screening in the care of patients with HIV-relatedconditions.