Abstract
BackgroundCo-receptor tropism (CRT) in patients with a long history of HIV-1 infection and antiretroviral treatment has been rarely investigated to date. The aim of this study was to determine the prevalence of X4 and R5 strains in patients with a >15-year follow-up and to investigate the demographical, viral, immunological, clinical and therapeutic determinants of CRT in this population. The possible influence of CRT on the inflammation state related to chronic HIV infection was also examined.MethodsA total of 118 HIV-1 infected patients with an initial HIV-1-positive test before 1997, and still on follow-up, were enrolled and consecutively submitted to blood sampling. Of these, 111 were on antiretroviral therapy and 89/111 (80.2%) had a plasma viral load (pVL) <25 copies/ml at testing. HIV-1 DNA was extracted and amplified from PBMCs for env gp120 sequencing. CRT was assigned by using geno2pheno and isolates were classified as X4 (FPR ≤20%) or R5 (FPR >20%). Level of serological inflammation biomarkers including IL-6, hsPCR, and D-dimers were measured.ResultsAn X4 virus was evidenced in HIV-1 proviral DNA of 50 patients (42%) while the remaining 68 patients were classified as R5. The median follow-up was 19 years (range 15–25). No association was observed between CRT and sex, age, nationality, subtype, HIV risk factor, HBV/HCV co-infection, baseline CD4+ cell count and pVL, overall duration of antiretroviral therapy, past exposure to mono-or dual therapies, and duration of NNRTI or PI-based therapy. The presence of an X4 strain was associated with CD4 nadir (p = 0.005), CD4 absolute count over time (p < 0.001), and cumulative positive (copy/years) viremia (p <0.001) during the whole patient history. No differences were found between R5 and X4 patients regarding inflammation marker levels including Il-6, hsPCR and D-dimers.ConclusionsAn archived X4 virus was demonstrated in 42% of patients with a >15-year-history of HIV infection. This presence was clearly associated with a greater exposure to positive viremia and a poorer CD4 trend over time compared to R5, independent of type and duration of antiretroviral treatment. CRT does not seem to influence the inflammation rate of patients aging with HIV.
Highlights
Co-receptor tropism (CRT) in patients with a long history of Human immunodeficiency virus type 1 (HIV-1) infection and antiretroviral treatment has been rarely investigated to date
The third variable (V3) region of gp120 is responsible for the differential C-X-C chemokine receptor type 4 (CXCR4) or C-C chemokine receptor type 5 (CCR5) co-receptor binding to HIV-1, and genotypic methods and bioinformatic tools based on V3 sequencing have been developed to facilitate the prediction of co-receptor tropism (CRT) [1]
A total of 50 (42%) patients showed a CXCR4-using virus (X4) virus in their HIV-1 proviral DNA while the remaining 68 patients were classified as CCR5-using virus (R5)
Summary
Co-receptor tropism (CRT) in patients with a long history of HIV-1 infection and antiretroviral treatment has been rarely investigated to date. The time span for seroconversion to AIDS does not differ significantly between individuals with pure R5 variants and those with non-R5 (pure X4 and dual-mixed, DM) variants [8] This shift might be the consequence, rather than the cause, of immunological deterioration which weakens the selective pressure, promoting non-R5 variants in vivo. It is unknown if X4 variants emerge from latency many years after an initial independent transmission or, more likely, if they evolve from preexisting R5 variants through a progressive acquisition of a broader receptor affinity [9]. When patients initiate antiretroviral therapy (ART), both increased and decreased frequencies of X4 viruses have been reported [10,11,12,13,14]; in addition, even if the presence of CRT does not seem to predict treatment success [15], recent cross-sectional studies have demonstrated X4 strains in 40%-55% of patients with antiretroviral exposure and therapy failure [16,17,18,19]
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