To investigate this potentially increased proportion of pati

To investigate this potentially increased proportion of patients with rapid progression to AIDS over the last decade in Cuba, we set up an exploratory study evaluating the association of rapid progression with epidemiological, clinical, viral and immunological parameters, comparing three groups of patients. The first two groups were newly diagnosed patients with an HIV negative test less than three years earlier recruited prospectively who within 3years after seroconversion either were already diagnosed with AIDS (AIDS-RP) or were still AIDS-free (non-AIDS) and chronically infected HIV-1 patients with AIDS recruited retrospectively (chronic-AIDS).
Patients and Methods
Results
Discussion It has been speculated that inter-subtype PCI32765 may give rise to more pathogenic strains if genomic fragments from different subtypes join together in a better replicating virus, but no direct evidence for this scenario has so far been found. CRF19_cpx is a genetic (Casado et al., 2005) form hitherto only reported in Cuba, but with evidenced central African ancestry (Thomson and Nájera, 2005; Casado et al., 2005; Delatorre and Bello, 2013). Recently, clinicians in Cuba noted an increasing trend of rapid progression to AIDS (<3years since seroconversion) (Abrahantes et al., 2010). Here, we propose that this increase is at least in part due to the spread of CRF19_cpx, which we found exclusively associated with rapid progression to AIDS (within 3years of infection), whereas for other subtypes and CRFs, the disease progression was distributed as is generally seen in other parts of the world. We set up an exploratory study in Cuba to investigate the association of rapid progression with epidemiological, clinical, viral and immunological parameters, comparing three groups of patients. The first two groups were recruited prospectively who at sampling within 3years after seroconversion either were already diagnosed with AIDS (AIDS-RP) or who were still AIDS-free (non-AIDS) and chronically infected HIV-1 patients with AIDS recruited retrospectively and sampled at AIDS diagnosis (chronic-AIDS). Bayesian network analysis showed that rapid progression to AIDS in Cuba, being infected with CRF19_cpx, having oral candidiasis, and having higher levels of RANTES are strongly linked. CRF19_cpx was exclusively found among rapid progressors. Compared to other patients in Cuba, CRF19_cpx infected patients have a higher viral load at comparable times since infection, higher levels of RANTES and are more frequently co-infected with oral candidiasis. Additionally, the virus at sampling had higher estimated protease fitness and was predominantly using the CXCR4 co-receptor, potentially explaining the rapid disease progression. Surprisingly however, even when restricting the analysis to the 52 rapid progressors only, CRF19 infection was significantly associated with oral candidiasis, CXCR4 co-receptor use prediction, higher RANTES levels, higher protease fitness at sampling and higher viral load at HIV diagnosis, whereas viral load at sampling was not. Together the higher viral load and higher estimated in vivo fitness of the viral protease suggest that CRF19 is an evolutionary fit virus. However, confirmation by a phenotypic assay is still warranted. CRF19_cpx is composed of subtype D fragments (C-part of Gag, PR, RT and nef), subtype A fragments (N-part of Gag, Integrase, Env) and subtype G fragments (Vif, Vpr, Vpu and C-terminal part of Env) (Casado et al., 2005). Several studies have reported the association of HIV subtype D with faster disease progression and subtype A with slower disease progression (Baeten et al., 2007; Kaleebu et al., 2002; Kiwanuka et al., 2008). The probability of having an CXCR4-using virus is higher in subtype D than in subtype A infections in non-AIDS clinical status (Kaleebu et al., 2007), suggesting an earlier switch to CXCR4 since dual tropism is not common in subtype D (Tscherning et al., 1998). These findings cannot explain our observations since in CRF19_cpx, the env region responsible for CXCR4 tropism is derived from subtype A. The high viral load, the higher production of RANTES (known to block CCR5 receptors) perhaps resulting from the high viral load (Annunziato et al., 2000) and/or the co-infections (Huang and Levitz, 2000), might be the reason for the high prevalence of CXCR4 use in this CRF19_cpx, and this may be the cause of the rapid disease progression. This high viral load may be related to and potentially caused by the high protease fitness we observed in CRF19_cpx, and thus could suggest a more important role of pol (subtype D portion), and especially of protease, in disease progression, as compared to the env region (subtype A portion) of CRF19_cpx.