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ObjectiveCXCR4 (X4)-tropic HIV-1 was found previously to herald CD4 + cell depletion and disease progression in individuals who were antiretroviral-naive or took combination antiretroviral therapy (cART) for less than 5 years. We updated this finding by investigating whether the deleterious effect of X4-tropic strains is mitigated by long-term cART.DesignWe examined morbidity and mortality in relation to HIV-1 tropism and cART in 529 participants followed up to 18 years in the Women's Interagency HIV Study; 91% were women of color.MethodsPlasma-derived HIV-1 tropism was determined genotypically.ResultsWe categorized participants according to the number of visits reported on cART after initiation. Group 1: three or less visits, 74% of these participants reporting no cART; group 2: at least four visits and less than 70% of visits on cART; group 3: at least 70% of visits on cART. AIDS mortality rates for participants in each group with X4 virus compared with those with R5 virus exclusively were, respectively: 62 vs. 40% ( P  = 0.0088); 23% vs. 22% [nonsignificant (NS)]; 7% vs. 14% (NS). Kaplan-Meier curves showed accelerated progression to AIDS death or AIDS-defining illness in participants with three or less cART visits and X4 viruses ( P  = 0.0028) but no difference in progression rates stratified by tropism in other groups. Logistic regression found that HIV-1 suppression for at least 10 semiannual visits (≥5 years total) mitigated X4 tropism's deleterious effect on mortality, controlling for maximal viral load, and CD4 + nadir.ConclusionLong-term cART markedly mitigated the deleterious effect of X4 viruses on AIDS morbidity and mortality. Mitigation was correlated with duration of viral suppression, supporting HIV-1 suppression as a crucial goal.

Background: Since only a few studies have been conducted on the factors associated with different HIV-1 tropisms in low-level viral load HIV-1 infections in China, we investigated the sequences of HIV-1 V3 loop in prevalent HIV-1 subtypes and factors related to HIV-1 tropism and immune recovery in HIV-1 infections after 6 months of highly active antiretroviral therapy (HAART) in Guangdong, China. Methods: Plasma samples with HIV-1 RNA of 400-999 copies/mL were collected. We analyzed the amino acid sequence of the V3 loop by in silico prediction algorithms. Mann-Whitney and Chi-square tests were used for statistical comparison. Furthermore, logistic regression and multiple linear regression were used, respectively, for factors associated with 351 HIV-1 tropism and immune recovery of 67 cases with continued CD4+ T cell count during HAART. Results: There was a lower percentage of HIV-1 R5-tropic virus in CRF01_AE (66.3%) (p < 0.0001) and CRF55_01B (52.6%) (p < 0.0001) compared with both CRF07_BC (96.1%) and CRF08_BC (97.4%), respectively. Compared with the R5- tropic virus, higher proportions of IIe8/Val8, Arg11/Lys11, and Arg18/His18/Lys18 were observed in the X4-tropic virus of CRF01_AE and CRF07_BC (p < 0.0001). The baseline CD4+ T cell count (p < 0.0001) and baseline CD4+ T/CD8+ T ratio (p = 0.0006) of all R5-tropic infections were higher than those in the X4-tropic infection. The baseline CD4+ T cell count (odds ratio [OR] 0.9963, p = 0.0097), CRF07_BC (OR 0.1283, p = 0.0002), and CRF08_BC (OR 0.1124, p = 0.0381) were associated with less HIV-1 X4-tropism. The baseline CD4+ T cell count was a positive factor (p < 0.0001) in the recovery of CD4+ T cell count during HAART. Conclusion: R5-tropism represented the majority in low-level viral load HIV-1 infections receiving HAART for more than 6 months in Guangdong, China. The baseline immune level in the HIV-1 R5-tropic infections was higher than that in the X4-tropic infections. The amino acids of the 8th, 11th, and 18th of the HIV-1 V3 loop were more variable in the X4-tropic HIV-1. CRF01_AE, CRF55_01B, and lower baseline CD4+ T cell count were associated with more HIV-1 X4-tropism. The immune recovery during HAART was positively related to baseline CD4+ T cell count. [ABSTRACT FROM AUTHOR]

Integrase-strand-transfer inhibitors (INSTIs) are known to rapidly reduce HIV-1 plasma viral load, replication cycles, and new viral integrations, thus potentially limiting viral evolution. Here, we assessed the role of INSTIs on HIV-1 V3 evolution in a cohort of 89 HIV-1-infected individuals starting an INSTI- (N = 41, [dolutegravir: N = 1; elvitegravir: N = 3; raltegravir: N = 37]) or a non-INSTI-based (N = 48) combined antiretroviral therapy (cART), with two plasma RNA V3 genotypic tests available (one before [baseline] and one during cART). V3 sequences were analysed for genetic distance (Tajima-Nei model) and positive selection (dN/dS ratio). Individuals were mainly infected by B subtype (71.9%). Median (interquartile-range, IQR) plasma viral load and CD4 + T cell count at baseline were 4.8 (3.5–5.5) log10 copies/mL and 207 (67–441) cells/mm3, respectively. Genetic distance (median, IQR) between the V3 sequences obtained during cART and those obtained at baseline was 0.04 (0.01–0.07). By considering treatment, genetic distance was significantly lower in INSTI-treated than in non-INSTI-treated individuals (median [IQR]: 0.03[0.01–0.04] vs. 0.05[0.02–0.08], p = 0.026). In line with this, a positive selection (defined as dN/dS ≥ 1) was observed in 36.6% of V3 sequences belonging to the INSTI-treated group and in 56.3% of non-INSTI group (p = 0.05). Multivariable logistic regression confirmed the independent correlation of INSTI-based regimens with a lower probability of both V3 evolution (adjusted odds-ratio: 0.35 [confidence interval (CI) 0.13–0.88], p = 0.027) and positive selection (even if with a trend) (adjusted odds-ratio: 0.46 [CI 0.19–1.11], p = 0.083). Overall, this study suggests a role of INSTI-based regimen in limiting HIV-1 V3 evolution over time. Further studies are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Highlights • Assessment of HIV-1 coreceptor usage with Geno2Pheno[coreceptor] (G2P[c]) algorithm. • Performance of G2P[c] for prediction of tropism with subtype A/CRF02_AG vs. subtype B. • Gold-standard tropism assignment by a phenotypical homebrew single-cycle assay. • Analysis of discrepant genotype-phenotype results by Next Generation Sequencing. Abstract Background Assessment of human immunodeficiency virus type 1 (HIV-1) coreceptor usage is required prior to treatment with the CCR5 antagonist maraviroc to exclude the presence of CXCR4-using (X4) strains. Genotype-based interpretation systems are mostly designed on subtype B and have been reported to be less accurate for subtype A/CRF02_AG. Objectives To evaluate the performance of the widely used Geno2Pheno[coreceptor] (G2P[c]) algorithm for prediction of coreceptor usage with subtype A/CRF02_AG vs. subtype B. Study design Co-receptor tropism of 24 subtype A/CRF02_AG and 24 subtype B viruses was measured phenotypically by a homebrew single-cycle assay and genotypically by using G2P[c]. Samples with discrepant genotype-phenotype results were analyzed by next generation sequencing (NGS) and interpreted by the NGS Geno2Pheno algorithm (G2P[454]). Results At 10% false positive rate (FPR), the G2P[ c ]/phenotype discordance rate was 12.5% (n = 3) for subtype A/CRF02_AG and 8.3% (n = 2) for subtype B. Minority X4 species escaping detection by bulk sequencing but documented by NGS explained the two subtype B and possibly one subtype A/CRF02_AG discordant case. The other two subtype A/CRF02_AG miscalled by G2P[c] could be explained by X4 overcalling at borderline FPR and/or by algorithm failure. Discussion Our study did not demonstrate relevantly higher G2P[c] inaccuracy with subtype A/CRF02_AG with respect to subtype B. Genotype/phenotype discordances can be due to different reasons, including but not limited to, algorithm inaccuracy. Very large genotype/phenotype correlation panels are required to detect and explain the reason for any consistent difference in genotypic tropism prediction for subtype A/CRF02_AG vs. subtype B. [ABSTRACT FROM AUTHOR]

Background The influence of HIV-1 co-receptor usage on the course of therapy in subjects fully responding to ART has been poorly investigated. Objectives To explore the relationship between co-receptor tropism and cellular reservoir size, residual viremia and subsequent virological outcome in ART-treated patients with HIV-1 RNA stable <50 copies/mL. Study design Viral co-receptor usage was predicted by viral env DNA sequencing with geno2pheno interpretation (FPR20%) and classified as R5 and non-R5. Total blood-associated HIV-1 DNA levels (log 10 copies/10 6 leukocytes) were measured by qRT-PCR (5′LTR). Residual plasma viremia was categorized as detectable (1–49 cps/mL) or undetectable (<1 copy/mL). Virological rebounds (any HIV-1 RNA >50 copies/mL) were evaluated over 96 weeks. Results The study included 116 subjects. Patients with R5 virus (n = 59) and non-R5 virus (n = 57) were homogeneous for the main characteristics except for the lower nadir CD4 cell count in the non-R5 group. Patients with non-R5 variants showed higher levels of HIV-1 DNA as compared to patients with R5 virus: mean 2.47 (95% CI 2.37–2.56) vs 2.17 (2.08–2.26) (p < 0.001). Moreover, a higher proportion of patients in the non-R5 group displayed detectable residual viremia with respect to the R5-group (54.4% vs 32.2%, p = .016). Detectable residual viremia was found to be significantly associated with viral rebounds. Conclusion The presence of non-R5 viral DNA variants is related to a higher probability of residual viremia and to a larger size of the cellular viral reservoir in this setting. These data highlight a potential role of viral tropism in the monitoring of HIV-1 infection in virologically controlled subject. [ABSTRACT FROM AUTHOR]

Background: Since only a few studies have been conducted on the factors associated with different HIV-1 tropisms in low-level viral load HIV-1 infections in China, we investigated the sequences of HIV-1 V3 loop in prevalent HIV-1 subtypes and factors related to HIV-1 tropism and immune recovery in HIV-1 infections after 6 months of highly active antiretroviral therapy (HAART) in Guangdong, China., Methods: Plasma samples with HIV-1 RNA of 400-999 copies/mL were collected. We analyzed the amino acid sequence of the V3 loop by in silico prediction algorithms. Mann-Whitney and Chi-square tests were used for statistical comparison. Furthermore, logistic regression and multiple linear regression were used, respectively, for factors associated with 351 HIV-1 tropism and immune recovery of 67 cases with continued CD4 + T cell count during HAART., Results: There was a lower percentage of HIV-1 R5-tropic virus in CRF01&#95;AE (66.3%) ( p  < 0.0001) and CRF55&#95;01B (52.6%) ( p  < 0.0001) compared with both CRF07&#95;BC (96.1%) and CRF08&#95;BC (97.4%), respectively. Compared with the R5-tropic virus, higher proportions of IIe8/Val8, Arg11/Lys11, and Arg18/His18/Lys18 were observed in the X4-tropic virus of CRF01&#95;AE and CRF07&#95;BC ( p  < 0.0001). The baseline CD4 + T cell count ( p  < 0.0001) and baseline CD4 + T/CD8 + T ratio ( p  = 0.0006) of all R5-tropic infections were higher than those in the X4-tropic infection. The baseline CD4 + T cell count (odds ratio [OR] 0.9963, p  = 0.0097), CRF07&#95;BC (OR 0.1283, p  = 0.0002), and CRF08&#95;BC (OR 0.1124, p  = 0.0381) were associated with less HIV-1 X4-tropism. The baseline CD4 + T cell count was a positive factor ( p  < 0.0001) in the recovery of CD4 + T cell count during HAART., Conclusion: R5-tropism represented the majority in low-level viral load HIV-1 infections receiving HAART for more than 6 months in Guangdong, China. The baseline immune level in the HIV-1 R5-tropic infections was higher than that in the X4-tropic infections. The amino acids of the 8th, 11th, and 18th of the HIV-1 V3 loop were more variable in the X4-tropic HIV-1. CRF01&#95;AE, CRF55&#95;01B, and lower baseline CD4 + T cell count were associated with more HIV-1 X4-tropism. The immune recovery during HAART was positively related to baseline CD4 + T cell count., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Lan, Li, He, Meng, Li and Chen.)