HIV human immunodeficiency virus type I (HIV-1) entry inhibitor potency is dependent on viral co-receptor tropisms and thereby tropism determination is clinically important. However, phenotypic tropisms of HIV-1 non-B subtypes have been poorly investigated and the genotypic prediction algorithms remain insufficiently validated. To clarify this issue, we recruited 52 treatment-naïve, HIV-1-infected patients in Tanzania, where multiple HIV-1 non-B subtypes co-circulate. Sequence analysis of 93 infectious envelope clones isolated from their plasma viral RNA revealed the co-circulation of subtypes A1, C, D, and inter-subtype recombinant forms (isRFs). Phenotypic tropism assays revealed that lentivirus reporters pseudotyped with 75 (80.6%) and 5 (5.4%) envelope clones could establish infection toward U87.CD4 cells expressing CCR5 (R5) and CXCR4 (X4), respectively; whereas the remaining 13 (14%) clones could infect both cells. Genotypic analyses by widely used algorithms including V3 net charge, Geno2pheno, WebPSSM, and PhenoSeq showed that almost all phenotypic X4-tropic clones and only 15 of 75 phenotypic R5-tropic clones were concordantly predicted. However, the remaining 60 phenotypic R5-tropic clones were discordantly predicted by at least one algorithm. In particular, 2 phenotypic R5-tropic clones were discordantly predicted by all algorithms tested. Taken together, the results demonstrate the limitation of currently available genotypic algorithms for predicting co-receptor inference among co-circulating multiple non-B subtypes and emerging isRFs. Also, the phenotypic tropism dataset presented here could be valuable for retraining of the widely used genotypic prediction algorithms to enhance their performance.
Small CD4-mimetic compound (CD4mc) interacts with the Phe43 cavity and triggers conformational changes, enhancing antibody-mediated neutralization and antibody-dependent cellular cytotoxicity (ADCC). Here, we evaluated the effect of YIR-821, a novel CD4mc, against clinical isolates, including both subtype B and non-B subtype viruses.
Background For over a decade, antiretroviral therapy (ART) in resource-limited countries was only recommended for patients with advanced HIV disease. We investigated this group of patients in order to determine any relationship between degree of immunosuppression during treatment initiation and the subsequent levels of inflammatory biomarkers, reservoir size and plasma marker of fungal translocation after achieving long-term virological control. Methods We analyzed 115 virally suppressed (female 83.5%) and 40 untreated (female 70%) subjects from Dar es Salaam, Tanzania. The size of HIV latent reservoir (proviral DNA copy) was determined using quantitative PCR. Inflammatory biomarkers; IL-6, IL-10, and soluble CD14 (sCD14), were measured using multiplex cytometric beads array. Antibody titers for Cytomegalovirus (CMV) and Epstein Barr virus (EBV), plasma level of 1-3-beta-d-Glucan (BDG) was measured using ELISA. High-sensitivity C-reactive protein (hsCRP) was measured using nephelometric method. Results The median age was 36 (IQR 32-44) and 47 (IQR 43–54) years in untreated and virally suppressed patients respectively. Median duration of treatment for virally suppressed patients was 9 years (IQR 7–12) and median baseline CD4 count was 147 cells/mm3 (IQR 65–217). Virally suppressed patients were associated with significantly lower plasma levels of IL-10, sCD14 and BDG (P < 0.05) when compared to untreated patients. However, plasma level of IL-6 was similar between the groups. Baseline advanced level of immunosuppression (CD4 < 100cells/cm3) was associated with significantly higher plasma level of IL-6 (P = 0.02), hsCRP (P = 0.036) and BDG (P = 0.0107). This relationship was not seen in plasma levels of other tested markers. Degree of baseline immunosuppression was not associated with the subsequent proviral DNA copy. In addition, plasma levels of inflammatory marker were not associated with sex, CMV or EBV antibody titers, treatment duration or regimen. Conclusions Our data suggest that advanced immunosuppression at ART initiation is associated with severity of inflammation and elevated fungal translocation marker despite long term virological control. Further studies are needed to evaluate the potential increased burden of non-AIDS comorbidities that are linked to elevated inflammatory and fungal translocation markers as a result of the policy of HIV treatment at CD4 count < 200 cells/cm3 implemented for over a decade in Tanzania.
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