Current HIV Research - Volume 10, Issue 8, 2012

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 immunodeficiency virus. However, whether a protective response can be induced by an infection with an immunodeficiency virus is still currently debated in the HIV-1 vaccine field. The aim of this study was to evaluate the protection against SHIV challenge in 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 envelope protein relative to the first challenge strain. Infection was monitored by measuring viral load and antibody response, as well as viral genome sequence analyses. Results: After first challenge, all the monkeys demonstrated high viral loads and specific antibody responses. Protection from 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. The susceptibility to super-infection was not correlated with neutralizing antibodies present at the time of exposure to the second virus. Conclusions: These findings indicate that different SHIV infection may confer different levels of protection against a second SHIV infection in Chinese monkeys. Understanding this protective response in SHIV infected macaques may shed a new light on HIV-1 vaccine development.

Binding of HIV gp120 to the chemokine coreceptor CXCR4 mediates signal transduction that promotes actin dynamics critical for the establishment of viral latency in resting CD4 T cells. To some extent, this gp120-mediated signal transduction 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. To determine 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, when we examined gp120 in a range of dosages, we found that in general, gp120 only attracts or repels blood resting CD4 T cells at a low level, and there is no clear pattern of dosage-dependency as normally seen in a typical chemokine. These irregularities of gp120 were observed in multiple donors. Nevertheless, gp120 aberrantly interferes with SDF-1-mediated T 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 stabilized with polyethylene glycol were used to study their cytotoxicity and antiviral activity against HIV-1 in the laboratory. The HeLa-CD4-LTR-B-gal cell line was used with gold nanoparticles to determine the cell viability using luminescent assay. The 50% cytotoxicity concentration, IC50 of gold nanoparticles was found to be 1.12 ± 0.05 mg/ml. M-tropic, T-tropic, dual tropic and resistant isolates were inhibited by gold nanoparticles and their inhibition concentration ranged from 0.05 to 0.12 mg/ml. The mechanism of gold nanoparticles against HIV-1 is not clear but it inhibits the HIV-1 fusion. In this study, the gold nanoparticles were used to analyze their mode of antiviral activity and the experimental results showed that they inhibit the viral entry by binding with gp120 and prevent CD4 attachment. These properties of gold nanoparticles make them as an effective antiviral inhibitor.

The nucleoside reverse transcriptase inhibitors (NRTIs), zidovudine (AZT) and stavudine (d4T) are thymidine analog 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 relative prevalence of TAM pathways and their associations with other NRTI resistance mutations acquired under the pressure of drug treatment in a large cohort of 1,876 patients infected with HIV-1 CRF01_AE attending the Infectious Disease Clinic, Chiang Mai University Hospital, Chiang Mai, Thailand, were studied. From 117 patients infected with HIV-1 CRF01_AE who had plasma HIV-1 RNA of ≥500 copies/mL, 69 patients had at least one TAM. The most common mutation associated with NRTI resistance was M184V/I (89.9%). The TAM-2 (89.9%) pathway occurred approximately two times more frequently than the TAM-1 (43.5%) pathway. The presence of TAM and the TAM-1 pathway was significantly 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 than the TAM-1 pathway by thymidine analog drugs in HIV-1 CRF01_AE-infected patients, while the TAM-1 pathway occurred more frequently than the TAM-2 pathway in such patients with AZT-based treatment. Routine monitoring of plasma 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 to second-line regimens containing a ritonavir-boosted protease inhibitor.

Background: Single nucleotide polymorphism of the hepatic cytochrome P450 isoenzyme 2B6 (CYP2B6) gene is a cause of variation in plasma efavirenz (EFV) concentrations. We aimed to determine the allelic distribution of CYP2B6 gene, plasma levels of EFV, the prevalence of clinical depression, and their correlations in northern Thai population. Methods: This was a cross-sectional study of HIV-infected patients on EFV-containing antiretroviral regimens for ≥48 weeks. 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 in 49%, 37%, and 14% of patients, respectively. The allele frequency of CYP2B6-516 G to T replacement was 32.5%. The median plasma EFV concentration was 2,616 ng/mL (IQR 1,851-3,742); 79% had EFV plasma concentrations from 1,000 to 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 with high plasma EFV levels. Nineteen patients had depression; 13 of 18 (72%) with mild and one with major depression had normal 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 strongly associated with inter-individual drug levels variation.

Despite the remarkable success of combination antiretroviral therapy, usually including the association of three antiretroviral drugs selected from two different classes, the possibility of treating HIV-infected patients with one single potent agent as simplified maintenance regimen has attracted clinicians and researchers over the past years. Monotherapy with one ritonavir-boosted protease inhibitor in subjects with persistently suppressed plasma HIV RNA offers several potential advantages, such as avoiding the long-term toxicity associated with nucleoside/nucleotide analog, reducing costs, preventing drug-drug interactions, and preserving future treatment options. Several controlled and uncontrolled studies have assessed efficacy and safety of this monotherapy strategy, and the majority of available data concern lopinavir/ritonavir and darunavir/ritonavir. The virological efficacy of these boosted protease inhibitors as monotherapy is slightly lower than that of standard therapy, but the risk of resistance development is minimal and the re-introduction of nucleoside analogues usually leads to a re-suppression of the plasma viral load. Even though currently there is no consensus about the clinical use of protease inhibitor monotherapy for the treatment of HIV infection, this strategy seems an option for selected patients on stable combination therapy, with persistently suppressed plasma viral load, and without a history of virologic failure while receiving protease inhibitors. The aim of this article is to review and summarize the most recent randomized and observational studies which have evaluated efficacy and safety of the protease inhibitor monotherapy.

Objectives: To describe the efficacy and tolerability of switching to raltegravir (RAL) in virologically suppressed 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 ≥ 6 months were switched to RAL (400 mg b.i.d). Reasons for change were toxicity (49.0%), drug interactions (6.1%) or convenience (28.6%) (switch from subcutaneous to oral treatment 22.4%, improvement of posology 3.4%). Patients were followed up to 24 months after switching to RAL. Primary end-points were tolerability and virological failure defined as two 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 (2.2 per 100 person-years [95%CI 0.9-4.6]), while AIDS occurred in 1, drug discontinuation in 4, 3 patients died and 10 were lost 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 were well tolerated and secured virologic suppression in the vast majority of patients.

Background: The course over time of different fibrosis parameters in HIV/HCV-coinfected patients who did not suppress HCV during anti-HCV therapy, and in patients who suppressed HCV but relapsed after treatment discontinuation is unclear. Methods: A total of 248 patients were included in the study (81 non-responders, 49 relapsers, and 118 control, untreated patients). Four primary non-invasive fibrosis indices (transient elastometry, APRI, Forns, and FIB4), as well as other fibrosis 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 this group there was a consistent increase in all fibrosis indices over time. On the contrary, treated patients experienced certain improvements in these indices during the period of treatment and a further worsening when the treatment was stopped, to reach the pretreatment values at the end of follow-up. Relapsers had also more favorable course than non-responders in each fibrosis parameter, but the differences were small and not statistically significant. Conclusions: HIV/HCV-coinfected patients who undergo unsuccessful anti-HCV treatment experience some improvement in liver fibrosis as compared to untreated patients, although the differences are small. Relapsers have also a more favorable fibrosis course than non-responders, but the differences are minimal. These improvements are only limited to the treatment period. Therefore the effect of unsuccessful treatment would only represent a transitory delay in fibrosis progression.

Background & Aims: Considering the disadvantages of liver biopsy, alternative noninvasive methods have been sought to assess the stage of liver fibrosis. The aim of this study is to determine the prevalence of different stages of chronic liver disease using noninvasive methods (transition elastography (Fibroscan®) and Forns and AST-to-platelet ratio index–APRI-indexes) in HCV/HIV-coinfected patients. Materials & Methods: An observational, cross-sectional, multicenter study conducted between September 2007 and May 2008. The study enrolled coinfected patients who had a transient elastography performed in the year of the study and/or biochemical 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 and Forns 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 for fibrosis 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 different fibrosis stages and it is significant. Transient elastography agrees with these indexes in the detection of significant and severe fibrosis.

Background: A possible viral etiology has been documented in the genesis of motor neuron disorders and acquired peripheral neuropathies, mainly due to the vulnerability of peripheral nerves and the anterior horn to certain viruses. 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 HIV infection, 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 with posterior distal paresis and atrophy in the left arm. We found electromyography tracings with deficits in the anterior horn of the spinal cord and peripheral nerves. Dysphagia and release of primitive reflexes were also identified. At the same time, the patient was informed to be HIV positive with high viral load. He received antiretroviral therapy, with load control but with no clinical remission. Conclusion: Motor Neuron disorders and peripheral neuropathy may occur in association with HIV infection. However, a causal relationship remains uncertain. It is noteworthy that the antiretroviral regimen may be implicated in some cases.

This study aimed to describe the epidemiological, immunological and molecular features of infection by the human T-lymphotropic virus-1/2 (HTLV-1/2) in individuals with HIV-1 in an urban area of Piaui State, Brazil. Exclusion criteria included patients under 18 years of age, pregnant women or Amerindians. Of 805 individuals analyzed by the serological method (ELISA) for the detection of anti-HTLV-1/2, 18 (2.24%) were positive, but only 13 (1.61%) were confirmed 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 was found with age (above 40 years: p = 0.002), minor surgeries (p = 0.004) and blood transfusion (p = 0.031). Quantification of the T CD4+/CD8+ lymphocytes and the HIV-1 viral load showed no significant association of T CD8 + lymphocyte levels with co-infection in the patients with HIV-1/HTLV-1. The sequencing of the LTR region and phylogenetic analysis indicated that the nine HTLV-1 strains belong to the Transcontinental subgroup of the Cosmopolitan group (1a), with a 83% (neighbor-joining) bootstrap value. The HTLV-2 strains were identified as subtype HTLV-2c, supported by a bootstrap value of 79%. Further studies in other population subgroups, such as blood donors and drug users, will be necessary to clarify the dissemination of HTLV-1/2 in Piauí and elucidate the developmental profile of the virus in the region.

Illicit drug use in HIV-infected patients can be linked to impairment of physical and mental health, low healthrelated quality of life, and suboptimal adherence to HIV treatment. This study aimed to evaluate the correlation of selfreport illicit drug use, urinalysis for cocaine and cannabis metabolites, and severity of dependence among HIV-infected patients on antiretroviral therapy (ART) in a treatment center in Brazil. Four hundred and thirty-eight outpatients of an HIV referral center were interviewed and assessed for drug use (lifetime, last year and last month). Urinalysis was performed to detect the presence of cocaine and cannabis metabolites in urine samples. Overall agreement between selfreport and urinalysis was almost 68% for cannabis and higher than 85% for cocaine. Positive urinalysis was significantly associated with more than once a week cannabis (p < .0001) and cocaine (p < .0001) use during the last-month. Severity of 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-related conditions.