CRF19_cpx is an Evolutionary fit HIV-1 Variant Strongly Associated With Rapid Progression to AIDS in Cuba

Abstract

BackgroundClinicians reported an increasing trend of rapid progression (RP) (AIDS within 3 years of infection) in Cuba.MethodsRecently infected patients were prospectively sampled, 52 RP at AIDS diagnosis (AIDS-RP) and 21 without AIDS in the same time frame (non-AIDS). 22 patients were sampled at AIDS diagnosis (chronic-AIDS) retrospectively assessed as > 3 years infected. Clinical, demographic, virological, epidemiological and immunological data were collected. Pol and env sequences were used for subtyping, transmission cluster analysis, and prediction of resistance, co-receptor use and evolutionary fitness. Host, immunological and viral predictors of RP were explored through data mining.FindingsSubtyping revealed 26 subtype B strains, 6 C, 6 CRF18_cpx, 9 CRF19_cpx, 29 BG-recombinants and other subtypes/URFs. All patients infected with CRF19 belonged to the AIDS-RP group. Data mining identified CRF19, oral candidiasis and RANTES levels as the strongest predictors of AIDS-RP. CRF19 was more frequently predicted to use the CXCR4 co-receptor, had higher fitness scores in the protease region, and patients had higher viral load at diagnosis.InterpretationCRF19 is a recombinant of subtype D (C-part of Gag, PR, RT and nef), subtype A (N-part of Gag, Integrase, Env) and subtype G (Vif, Vpr, Vpu and C-part of Env). Since subtypes D and A have been associated with respectively faster and slower disease progression, our findings might indicate a fit PR driving high viral load, which in combination with co-infections may boost RANTES levels and thus CXCR4 use, potentially explaining the fast progression. We propose that CRF19 is evolutionary very fit and causing rapid progression to AIDS in many newly infected patients in Cuba.

Comparative Evaluation of Subtyping Tools for Surveillance of Newly Emerging HIV-1 Strains

“…In addition to the epidemiological impact, the spread of HIV-1 subtypes is clinically relevant: HIV-1 clades show differences in pathogenesis and resistance pathways, with implications for clinical outcomes, diagnosis, viral quantification, and vaccine development (14)(15)(16)(17)(18)(19). With continuous discovery of new HIV-1 strains (https://www.hiv.lanl .gov/content/sequence/HIV/CRFs/CRFs.html) coupled with the increasing phylogeography and phylodynamics of non-B subtypes spreading into Western countries (6-8; see also WHO data at http://www.who.int/gho/hiv/en/), it would be of paramount importance to accurately identify newly emerging strains, both for efficient molecular epidemiological surveillance and for optimal clinical management of patients infected with diverse HIV-1 strains, particularly in Italy, where the migration rate is high (12,13).…”

Co-Receptor Tropism Determined by Genotypic Assay in HIV-1 Circulating in Cuba

“…However, a recent report from our group found that CRF19_cpx was associated with rapid progression to AIDS and one of the hypotheses for explaining this rapid progression was the finding of higher levels of RANTES and significantly more frequent proportion of X4 virus among the patients infected with this viral variant [20].…”

“…A false-positive rate (FPR) <5% are mainly X4 and ≥ 20% are mainly R5 variants. Therefore, we classified V3 loop sequences with FPR ≥ 20% as R5 viruses, with FPR ≥ 5% and <20% as dual-tropic viruses (R5X4) and with FPR <5% as X4 viruses as described previously [20,28,29].…”

“…Subtype B represents only a third of the Cuban epidemic and BG recombinants and various CRFs in Cuba are currently expanding [17][18][19]. Furthermore, a recent report showed that the viral variant CRF19_cpx was exclusively associated with rapid progression to AIDS in Cuban individuals [20].…”

Análisis genético de las mutaciones presentes en las poblaciones virales en pacientes con infección por VIH-1 en Ecuador

“…29 . Recientemente se describió una forma recombinante con rápida progresión a SIDA, como es el caso del CRF19_cpx, presente en la epidemia cubana 30,31 . Las diferencias encontradas en el presente estudio dado lo pequeña y variado de la muestra no se establecieron de forma significativa.…”