BACKGROUND A high copy number of CCL3L1, the most potent HIV-suppressive chemokine, associates with reduced HIV susceptibility. Whether CCL3L1 influences acquisition of multiple blood-borne infections (HCV, HIV-1, HBV) that occurs commonly among intravenous drug users (IDUs) is unknown. METHODS We determined CCL3L1 copy number by real-time PCR among 374 Caucasian IDUs from Estonia of whom 285 were HCV-positive, 208 HIV+, 177 HCV+/HIV+, and 57 HCV−/HIV−. RESULTS In univariate and multivariate analyses, HCV and HBV seropositivity, and duration of IDU each strongly predicted HIV seropositivity. A high CCL3L1 copy number (>2) associated with a 80% reduced risk of acquiring HIV, after adjusting for age, gender, HCV/HBV status, CCR5-Δ32 polymorphism and IDU duration (OR=0.20; 95% CI=0.09–0.45). By contrast, CCL3L1 gene dose did not influence HCV seropositivity. Among HCV+ IDUs, there was a 3.5-fold over- and 65% under-representation of a high CCL3L1 copy number among HCV+/HIV− and HCV+/HIV+ subjects, respectively. CONCLUSION Among IDUs exposed heavily to HCV/HIV, CCL3L1 copy number is a major determinant of HIV seropositivity, but not HCV seropositivity. The contrasting distribution of a protective high CCL3L1 copy number among HCV+/HIV− vs HCV+/HIV+ IDUs may reflect that HIV preferentially selects for subjects with a low CCL3L1 gene dose.

All non-B HIV-1 subtypes and circulating recombinant forms (CRFs) are characterized by several polymorphisms in protease (PR) region. In addition, in recent years the increasing use of antiretroviral treatment (ART) has rapidly raised the spread of transmitted drug resistance. We aimed to determine the presence of naturally occurring polymorphisms and transmitted drug resistance mutations (DRMs) in ART naïve HIV-1-positive subjects in Estonia. A total of 115 drug-naive HIV-1-infected subjects (mean age 27 years; 70% male; 65% infected via intravenous drug use and 34% by heterosexual contact) were enrolled. Viral genomic RNA from plasma was directly sequenced in PR, revertase (RT), and envelope (env) regions. Phylogenetic analysis of RT and env regions revealed that 89% and 3% of sequenced viruses belonged to CRF06_cpx and subtype A1, respectively, and 6% were described as unique recombinants (signed A1-06) between CRF06_cpx and subtype A1 viruses. No primary DRMs were found in PR or RT regions indicating the absence of transmitted drug resistance. The most common polymorphisms in the PR region were K14R, M36I, H69K, and L89M seen in 96%, 100%, 99%, and 100%, respectively. The clinical relevance of these polymorphisms in terms of success of ART has to be monitored in future clinical studies.

BackgroundUp to 90% HIV-1 positive intravenous drug users (IDUs) are co-infected with HCV. Although best recognized for its function as a major co-receptor for cell entry of HIV, CC chemokine receptor 5 (CCR5) has also been implicated in the pathogenesis of HCV infection. Here, we investigated whether CCR5 haplotypes influence HIV-1 and HCV seropositivity among 373 Caucasian IDUs from Estonia.MethodsOf these IDUs, 56% and 44% were HIV and HCV seropositive, respectively, and 47% were coinfected. 500 blood donors seronegative for HIV and HCV were also evaluated. CCR5 haplotypes (HHA to HHG*2) were derived after genotyping nine CCR2–CCR5 polymorphisms. The association between CCR5 haplotypes with HIV and/or HCV seropositivity was determined using logistic regression analysis. Co-variates included in the models were length of intravenous drug use, HBV serostatus and copy number of CCL3L1, the gene encoding the most potent HIV-suppressive chemokine and ligand for CCR5.ResultsCompared to IDUs seronegative for both HCV and HIV (HCV−/HIV-), IDUs who were HCV+/HIV- and HCV+/HIV+were 92% and 82%, respectively, less likely to possess the CCR5-HHG*1 haplotype, after controlling for co-variates (Padjusted = 1.89×10−4 and 0.003, respectively). This association was mostly due to subjects bearing the CCR5 HHE and HHG*1 haplotype pairs. Approximately 25% and<10% of HCV−/HIV- IDUs and HCV−/HIV- blood donors, respectively, possessed the HHE/HHG*1 genotype.ConclusionsOur findings suggest that HHG*1-bearing CCR5 genotypes influence HCV seropositivity in a group of Caucasian IDUs.

Natural polymorphisms of HIV-1, often associated with drug resistance, are widely described in protease and reverse transcriptase regions but data on their presence in the integrase region, especially in non-B subtypes, are still very limited. We aimed to characterize naturally occurring polymorphisms in the integrase region in 104 treatment-naive and 10 treatment-experienced patients infected predominantly with HIV-1 CRF06_cpx and its recombinant with subtype A1 and/or CRF03_AB viruses. No primary drug resistance mutations against integrase inhibitors were found, but resistance-associated polymorphisms such as V72I, L74I, V201I, and T206S were seen in more than 90% of viruses. Substitutions E157Q and E157K, associated with raltegravir resistance, were found in only two CRF06_cpx strains. We conclude that similar to other HIV-1 non-B subtypes, the CRF06_cpx and its recombinants with subtype A1 and CRF03_AB are rich in integrase region natural polymorphisms, which may impact the development of resistance against integrase inhibitors.

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