Current HIV Research - Volume 15, Issue 4, 2017

Background: The chemokine receptor CCR5 acts as a co-receptor for HIV binding and it is considered as an important target by CCR5 antagonists. Entry inhibitor based microbicides gain much importance nowadays as these drugs act at an early stage of HIV lifecycle and thus hinder the viral replication process in humans. The present study intends to identify a CCR5 antagonist which could be developed as a microbicide using computational approaches. Methods: The pharmacophore modeling and 3D QSAR studies was used to screen CCR5 antagonists with enhanced antagonist activity. The docking studies ranked the compounds according to their bind- ing affinity and molecular dynamics simulation validated the stability of the enzymeligand complex. Results: A five point pharmacophore hypothesis HHPRR (2 hydrophobic; 1 positively ionisable; 2 aromatic ring) was generated. A statistically significant 3D QSAR model with 3 PLS factors was gen- erated for common pharmacophore hypothesis HHPRR.3 with good correlation coefficient value (R2=0.7483). The docking studies revealed that molecular interaction of CCR5 antagonists having good binding affinity are better than the microbicides taken for this study. The QSAR maps revealed the regions as a combined effect of hydrogen bond donors, hydrogen bond acceptors and hydrophobic groups which denoted the substitution of groups indicating the favorable and unfavorable regions for antagonist activity of hydroxypiperidine derivatives. The docking analysis and molecular dynamics simulation screened and validated CCR5 antagonists. Conclusion: The present study was successful in identifying a CCR5 antagonist which could be developed as a microbicide.

Background: Host restriction factors are cellular proteins able to diminish or block viral replication in a cell-specific way. Objective and Method: We evaluated the distribution of single nucleotide polymorphisms (SNPs) in APOBEC3G (rs3736685, rs2294367) and CUL5 (rs7117111, rs7103534, rs11212495) genes, among 264 HIV-1 infected (HIV-1+) and 259 unexposed- uninfected individuals from Northeast Brazil, looking for a possible association with susceptibility to HIV-1 infection, viral load during treatment, CD4+ T cell count and therapeutic success of the antiretroviral treatment. Results: The rs11212495 CUL5 G allele and the CUL5 rs7103534-rs7117111 CG haplotype were more frequent among unexposed-uninfected than in HIV-1+ individuals, suggesting an association with a lower HIV-1 infection susceptibility. The APOBEC3G rs2294367 G/C genotype correlated with delayed viral load suppression. Our results showed a great heterogeneity in relation to the literature findings, possibly due to ethnic differences among the studied populations, sample size used in the studies and, also, to the type of controls, i.e. in our study used unexposed-uninfected rather than exposed-uninfected individuals (rare and considered gold standard for susceptibility studies). Conclusion: Our findings report genetic variants possibly associated with susceptibility to HIV-1 infection (CUL5 rs11212495, rs7103534, rs7117111) and partial viral load control (APOBEC3G rs2294367). Replica studies performed on higher number of subjects are envisaged to confirm our results.

Background: Lymphoproliferative disorders are frequently diagnosed in HIV-positive patients and severe infections may occur during antineoplastic treatments: the incidence and impact of such events are not well-characterized. Objective: To describe the occurrence and mortality of incident infections in HIV-positive individuals treated for lymphoproliferative disorders. Methods: A retrospective study in HIV-positive adults with lymphoproliferative disorders (2000- 2012) who were hospitalised to receive antineoplastic chemotherapy; antimicrobial prophylaxis with alternate day co-trimoxazole (800/160 mg) was administered to all individuals. Results: 103 patients were included: mostly males (81, 78.6%), Caucasians (101, 98.1%), with a median age of 43 years (39-51). Fifty-eight (56.3%) patients had non-Hodgkin's lymphoma (NHL), thirty-two (29.1%) had Hodgkin's lymphoma (HL) and ten patients (9.7%) had Burkitt's lymphoma (BL). Five year survival was 63.1%: the best survival rates were reported in HL (78.1%), followed by NHL (58.6%) and BL (50%). Forty-four patients (42.7%) developed 82 infections during follow up: identified causative agents were bacteria (35, 42.7%), viruses (28, 34.1%), mycobacteria (7, 8.5%), protozoa (7, 8.5%) and fungi (5, 6.1%). Cytomegalovirus infections (n=17, including 5 endorgan diseases) emerged 53 days after the diagnosis: multivariate analysis showed CD4+ cell count <100/uL as the only independently associated factor (plt;0.001, aOR=23.5). Two factors were associated with mortality risk: an IPI/IPS-score of >2 (p=0.004, aOR=6.55) and the presence of CMV disease (p=0.032, aOR=2.73). Conclusion: HIV positive patients receiving treatment for lymphoproliferative disorders suffer from a high incidence of infections and associated mortality risk. Tailored prophylactic strategies need to be considered in this setting.

Background: Genetic variations in Human leukocyte antigen C (HLA-C), Zinc ribbon domain containing 1 (ZNRD1) and its antisense RNA (ZNRD1-AS1) genes are known to influence the HIV-1 replication and disease progression. Objective and Method: We evaluated the distribution of HLA-C (rs10484554, rs9264942) and ZNRD1 (rs8321) and ZNRD1-AS1 (rs3869068), single nucleotide polymorphisms (SNPs) in 266 HIV-1-infected and 223 unexposed-uninfected individuals from Northeast Brazil and their relation to HIV-1 infection, CD4 T cells count and viral load pre-treatment. Results: HLA-C SNPs were in Linkage Disequilibrium (D’=0.84), constituting four possible haplotypes. Our results showed that HLA-C, ZNRD1 and ZNRD1-AS1 SNPs as well as HLA-C haplotypes frequencies were not significantly different between HIV-1-infected and unexposed-uninfected individuals. In addition, we analyzed HLA-C and ZNRD-1 and ZNRD1-AS1 SNPs considering CD4+ T cell counts and viral load before the antiretroviral treatment. Individuals carrying HLA-C rs9264942 TT genotype showed a significant increased level of HIV-1 viral load pre-treatment, in comparison with individuals carrying the CC genotype (p-value = 0.0092). Finally, we stratified our findings according to CCR5Δ32 allele presence along with the studied SNPs: no statistically significant influence over viral load pre-treatment has been found. Conclusion: The association between HLA-C rs9264942 SNP and viral load prior treatment in an admixed population from North East Brazil was in agreement with findings from previous studies obtained on different ethnic groups; however more studies should be conducted in order to clarify how HLA-C impair the HIV-1 replication

Background: HIV-infected homosexual men are more frequently diagnosed with Kaposi's sarcoma. With the increase of HIV-infected homosexual men in China, we urgently need to know the KS-related human herpesvirus (KSHV/HHV-8) seroprevalence in this population. To investigate HHV-8 prevalence among HIV-positive homosexual men, we recruited 183 patients naive of antiretroviral therapy (ART) whose blood samples presented with HIV-antibody positive as confirmed by western blot. Methods: HIV viral load was tested using Cobas TaqMan HIV-1 test Version 2.0, and CD4 T cell counts were tested using a Flow cytometry instrument. All HIV-positive blood samples were collected and screened for KSHV. Immunofluorescence (IFA) test was conducted for HHV-8-Specific antibodies (anti-LANA) in the plasma. HHV-8 DNA in whole blood cells of IFA-positive subjects was quantified with Real-time polymerase chain reaction (RT-PCR). Results: All samples showed HIV RNA positive. CD4+ T cell count was 23% cases (42/183) which showed ≤200 cells/μL, 51.3% cases (94/183) showed 201-500 cells/μL and 25.7% cases (47/183) showed ≥501 cells/μL. Immunofluorescence (IFA) test demonstrated an HHV-8 prevalence of 50.8% (93/183), among which 20.4% of the cases (19/93) were HHV-8 DNA positive. HHV-8 infection showed no difference among different age groups (p=0.96). Similarly, HHV-8 infection exhibited no significant difference among different HIV viral load groups (p=0.08). However, HHV-8 infection among different CD4+ T cell count showed significant difference (P=0.0004). Conclusion: This study showed a high seroprevalence of human herpesvirus 8 infection in HIVpositive homosexual men.

Background: Cytokines have been widely demonstrated to involve in the pathogenesis of AIDS and the mechanisms of antiretroviral therapy. Interleukin 27 (IL-27) is a new member of the IL-12 cytokine family and has been shown to interfere HIV-1 virus replication with controversial findings. This study is to investigate the dynamic changes in plasma IL-27 level and cell surface IL-27 receptor expression in HIV/AIDS patients who underwent HAART. Methods: Whole blood was collected from 34 HIV-positive/AIDS patients 0, 6, and 12 months after initiation of HAART and 27 healthy subjects. Plasma IL-27, IFN-γ, and IL-4 were measured by enzyme-linked immunosorbent assay, while peripheral blood CD3+CD4+ T cells count and the gp130 expressed CD3+CD4+cell were measured by flow cytometry. Results: The plasma IL-27 concentration, IFN-γ concentration, and percentage of positive gp130 CD4 cells were significantly decreased in previously treatment-naive HIV/AIDS patients compared to healthy controls, but gradually increased 6 and 12 months after initiation of HAART. Conversely, IL-4 levels were significantly increased in treatment-naive HIV/AIDS patients compared to healthy controls, but gradually decreased 6 and 12 months after HAART. The concentrations of plasma IL-27 were positively correlated with the percentage of gp130 positive CD4 cells (r=0.438, p=0.016). Both plasma IL-27 concentration and gp130 positive cell percentage were positively associated with peripheral blood CD3CD4+ T cell count (P<0.05 or P<0.01), but negatively associated with plasma HIV viral load (P<0.05 or P<0.01). Conclusion: IL-27 signaling (IL-27 and its receptor) may be involved in the pathogenesis of HIV infection and immune reconstitution in HIV/AIDS patients who underwent HAART. IL-27 may exert effects through regulating Th1 / Th2 ratio.

Background: Phagocytosis is regarded to be impaired in HIV-1 infected adults, leading to high frequency and severity of several infections in this population. Data is contradictory with regards to individual facets in HIV infection. Objective: Aim of this study was to assess the phagocytic activity during the natural course of HIV infection. Method: It is a longitudinal study assessing natural course and impairment of neutrophil and monocyte phagocytosis in both naïve and HAART treated patients. Results: A lower neutrophil phagocytic activity was recorded in naïve patients compared to treated patients. Interestingly, a downward trend of neutrophil phagocytic activity was recorded in both groups, irrespectively of HAART intake, within 48 weeks of observation. Conclusion: Defects of innate immunity appear to be present in HIV infected patients regarding phagocytic activity of monocytes and of neutrophils which seems to decline over time. These deficiencies are influenced by the levels of CD4 cell counts and viral load.

Background: Human milk banking has been promoted to provide donated breast milk for at-risk children whose mothers cannot breastfeed them but this effort was hindered by the advent of HIV epidemic. Objective: To estimate the seroprevalence of HIV, syphilis and hepatitis B in the blood of human milk donors registered in a major maternity hospital in the northern region of the Santa Catarina State, Brazil. Methods: A retrospective study included serological tests for HIV, syphilis and hepatitis B screening of milk donor candidates in the 2005-2015 period. The 95% confidence intervals were calculated using the Poisson distribution. Results: For HIV, the prevalence per 100.000 pregnant women was 155, 170 and zero over the three periods analyzed (2005-2009, 2010-2012 and 2013-2015), respectively. Syphilis prevalence per 100,000 pregnant women was 509, 460 and 1749 in the three periods analyzed. For the HBsAg marker of recent hepatitis B infection, the prevalence on the same scale was 254, 231 and 299, respectively, while the anti-HBc prevalence, a marker of lifetime risk for hepatitis B infection, was 7339 in the 2010-2012 period and 3874 in the 2013-2015 period. Conclusion: High prevalence of HIV, syphilis and hepatitis B was found for the 2005-2015 period among breastfeeding mothers who offered to donate their exceeding milk to a human milk bank in Brazil. Despite apparent elimination of the HIV by the end of the period, the decline was not statistically significant. There was no significant change in the acute hepatitis B prevalence over time but the increased syphilis prevalence in the most recent period was statistically significant.

Background: First line antiretroviral therapy in a resource-limited setting consists of nucleotide and non-nucleotide reverse transcriptase inhibitors. Protease inhibitors are the hub of second line therapy. The decision to change antiretroviral therapy for a patient is frequently presumptive because of the lack of genotypic resistance tests in routine follow-up. We describe here the resistance profiles observed in patients with varying terms of antiretroviral therapy in Cameroon after implementation of HIV genotypic resistance testing in routine practice. Methods: HIV genotypic resistance testing was carried out on consecutive samples received between August 2013 and November 2015. Protease (Prot) and reverse transcriptase (Rt) genes of the HIV genome were amplified, sequenced and analyzed for drug resistance mutations following the algorithm set up by the French National Agency for research on HIV/AIDS and viral hepatitis. Results: Specimens from a total of 167 patients infected with non-B HIV subtypes were received during the study period. Overall 61.7% patients had viral loads of more than 3log copies/ml, suggesting treatment failure. Among the 72 patients on first line, 56 (77.8%) were resistant to Lamivudine, 57 (79.1%) to Efavirenz and 58 (80.6%) to Nevirapine. Overall, more patients (75.0%) on first line antiretroviral therapy harbored multi-drug resistance compared to their counterparts on second line (25.8%). Conclusion: This study revealed that a group of patients with antiretroviral therapy failure harbored multi-drug resistance mutations related to the majority of drugs in the first line regimen. Therefore, HIV resistance testing could be a useful tool to improve HIV care in resource limited settings like Cameroon where treatment options are limited.