Predicted HIV-1 coreceptor usage among Kenya patients shows a high tendency for subtype d to be cxcr4 tropic

Abstract

BackgroundCCR5 antagonists have clinically been approved for prevention or treatment of HIV/AIDS. Countries in Sub-Saharan Africa with the highest burden of HIV/AIDS are due to adopt these regimens. However, HIV-1 can also use CXCR4 as a co-receptor. There is hence an urgent need to map out cellular tropism of a country’s circulating HIV strains to guide the impending use of CCR5 antagonists.ObjectivesTo determine HIV-1 coreceptor usage among patients attending a comprehensive care centre in Nairobi, Kenya.MethodsBlood samples were obtained from HIV infected patients attending the comprehensive care centre, Kenyatta National Hospital in years 2008 and 2009. The samples were separated into plasma and peripheral blood mononuclear cells (PBMCs). Proviral DNA was extracted from PBMCs and Polymerase Chain reaction (PCR) done to amplify the HIV env fragment spanning the C2-V3 region. The resultant fragment was directly sequenced on an automated sequencer (ABI, 3100). Co-receptor prediction of the env sequences was done using Geno2pheno [co-receptor], and phylogenetic relationships determined using CLUSTALW and Neighbor Joining method.ResultsA total of 67 samples (46 treatment experienced and 21 treatment naive) were successfully amplified and sequenced. Forty nine (73%) sequences showed a prediction for R5 tropism while 18(27%) were X4 tropic. Phylogenetic analysis showed that 46(69%) were subtype A, 11(16%) subtype C, and 10(15%) subtype D. No statistical significant associations were observed between cell tropism and CD4+ status, patient gender, age, or treatment option. There was a tendency for more X4 tropic strains being in the treatment experienced group than the naive group: Of 46 treatment experiencing participants, 14(30%) harboured X4, compared with 4(19%) of 21 of the treatment-naïve participants, the association is however not statistically significant (p = 0.31). However, a strong association was observed between subtype D and CXCR4 co- receptor usage (p = 0.015) with 6(60%) of the 10 subtype D being X4 tropic and 4(40%) R5 tropic.ConclusionHIV-1 R5 tropic strains were the most prevalent in the study population and HIV infected patients in Kenya may benefit from CCR5 antagonists. However, there is need for caution where subtype D infection is suspected or where antiretroviral salvage therapy is indicated.

Non-R5-tropic HIV-1 in subtype A1 and D infections were associated with lower pretherapy CD4+ cell count but not with PI/(N)NRTI therapy outcomes in Mbarara, Uganda

“…Previous studies tend to focus on only two of the three factors at a time: In terms of the relationship between HIV-1 subtype and pre-therapy CD4 count, our observation agrees with previous reports that pre-therapy subtype D infections are “more aggressive” than subtype A1 by being associated with a lower baseline CD4 count [2,3]. In terms of the relationship between HIV-1 subtype and viral tropism, our observation agrees with previous reports that subtype D is associated with a higher prevalence of non-R5-tropic viruses [7,8,11–14]. In terms of the relationship between viral tropism and pre-therapy CD4 count, our observation agrees with previous reports that non-R5 infections are associated with lower CD4 count [10,27,28].…”

“…Unlike any of the aforementioned studies [2,3,7,8,10–14,27,28] that focused on only two factors at a time, we statistically examined the relationship between all three factors (subtype, tropism and pre-therapy CD4 count) by comparing baseline correlates and clinical outcomes between R5 infections in subtype A1 against D, as well as non-R5 infection in subtype A1 against D, and found no significant differences between groups. In other words, an infection that was both subtype D and non-R5 did not show a synergistic and negative effect at baseline when compared to subtype A non-R5 infections, suggesting that viral tropism, not subtype, drove the previously observed association between both non-R5 tropism and subtype D with a lower pre-therapy baseline CD4 count.…”

“…Both subtype D and non-R5 are independently associated with a faster disease progression [2,3,7,8]. Numerous studies have shown that subtype D viruses are more likely to be non-R5-tropic [7,8,11–14], and non-R5-tropic subtype D infections in Ugandan babies is linked to higher mortality [12]. These observations lead to the question of whether an infection that is both subtype D and non-R5 would lead to synergistic increase in disease progression.…”

HIV subtype is not associated with dementia among individuals with moderate and advanced immunosuppression in Kampala, Uganda

“…CXCR4 viruses arise with more advanced immunodeficiency in 40-50% of HIV infected adults, and are associated with rapid HIV disease progression including neurological symptoms such as dementia (Gabuzda & Wang 2000). Several recent studies from Uganda (Kaleebu et al 2007) and Kenya (Wambui et al 2012) demonstrate that the probability of having a CXCR4 virus was higher in HIV subtype D infections compared to subtype A infections. For example, 60% of HIV subtype D cases had CXCR4 co-receptor usage compared to 22% of HIV subtype A cases with CXCR4 co-receptor usage.…”

Bioinformatic Analysis of HIV-1 Entry and Pathogenesis

“…The new combined 11/25 and net charge rules for subtype D gave a better performance (92% concordance with 75% sensitivity and 95% specificity) [295]. This new subtype D combined algorithm also showed an improved viral tropism prediction exhibiting 85% concordance with the phenotype assay, with 68% sensitivity and 95% specificity, as compared with geno2pheno and the original combined 11/25 and net charge algorithm, validated by an independent data set of 67 subtype D sequences retrieved from GenBank [296]. …”