Background As access to antiretroviral drugs increases in developing countries, it will become increasingly important to monitor the emergence of resistance and to define the molecular pathways involved to identify optimal therapeutic regimens. Methods We performed genotypic resistance testing on plasma obtained from 101 HIV-infected treatment-naı¨venaı¨ve individuals from Mali. Genotyping was carried out using the Virco protocols and HXB2 was used as the reference strain. Results CRF02_AG was the most common subtype, present in 71.3% of our patient population. Other subtypes included B, C, G, CRF06_CPX, CRF09_CPX, CRF01_AE, A2/CRF16_A2D, A1 and CRF13_CPX. A total of 9.9% [95% confidence interval (CI) 6.9-12.9%] of patients had at least one resistance mutation. The prevalences of mutations conferring resistance to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 5% (95% CI 0.7-9.2%), 6% (95% CI 1.3-10.6%) and 0%, respectively. The most frequent mutations were T215A/Y for NRTIs and K103N/T for NNRTIs. One patient harboured three NRTI resistance mutations and one NNRTI mutation. This is the first reported case of multi-drug-resistant viral transmission in Mali. Polymorphisms at protease codons 10I/V and 33F potentially associated with resistance were observed in 18.8% and 1% of patients, respectively. Several polymorphisms in the C-terminal domain of reverse transcriptase were observed: A371V (in 63.4% of patients), G335D (76.2%), E399D (10.9%) and G333E (1%). Conclusion Primary resistance was seen in 9.9% of subjects, which is higher than previously reported in Mali. Taking into consideration other polymorphisms in protease such as L10I/V and 33F, primary resistance could reach 28.7% (95% CI 19.9-37.5%). Our study reflects the need to monitor the evolution of resistance on a regular basis and trends of transmitted resistance.

BackgroundResistance to CCR5 inhibitors, such as maraviroc and vicriviroc is characterized by reduction of maximal percent inhibition which indicates the use of an inhibitor-bound conformation of CCR5 for human immunodeficiency virus-1(HIV-1) entry. It is accompanied by substitutions in gp120 and gp41. Variable domain 3 (V3) plays the most important role, but substitutions outside V3 could also be involved in phenotype resistance. In this work, we investigated how mutations in variable regions of the viral envelope protein gp120 can contribute to CCR5 inhibitor resistance.MethodsResistant isolates were selected by passaging CC1/85 and BaL viruses with sub-inhibitory MVC and VCV concentrations. Mutations in gp160 were identified and mutants containing V2 (V169M), V3 (L317W) and V4 (I408T) were constructed.ResultsMVC and VCV susceptibility and viral tropism were assessed by single cycle assay. Mutant I408T showed 4-fold change (FC) increase in the half maximal inhibitory concentration (IC50) to MVC, followed by L317W (1.52-FC), V169M (1.23-FC), V169M/I408T (4-FC) L317W/I408T (3-FC), V169M/L317W (1.30-FC), and V169M/L317W/I408T (3.31-FC). MPI reduction was observed for mutants I408T (85%), L317W (95%), V169M/I408T (84%), L317W/I408T (85%) and V169M/L317W/I408T (83%). For VCV, I408T increased the IC50 by 2-FC and few mutants showed MPI reduction less than 95%: I408T (94%), L317W/I408T (94%) and V169M/L317W/I408T (94%). All mutants remained R5-tropic and presented decreased infectivity.ConclusionsThese results suggest that mutations in the V4 loop of HIV-1 may contribute to MVC and VCV resistance alone or combined with mutations in V2 and V3 loops.

cHere, we evaluated the in vitro anti-HIV-1 activity of the experimental CCR5 inhibitor VCH-286 as a single agent or in combination with various classes of HIV-1 inhibitors. Although VCH-286 used alone had highly inhibitory activity, paired combinations with different drug classes led to synergistic or additive interactions. However, combinations with other CCR5 inhibitors led to effects ranging from synergy to antagonism. We suggest that caution should be exercised when combining CCR5 inhibitors in vivo.

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