High levels of divergent HIV-1 quasispecies in patients with neurological opportunistic infections in China

Department of Infectious Diseases, Beijing You'An Hospital, Capital Medical University, Beijing, 100069, China.
Journal of NeuroVirology (Impact Factor: 2.6). 07/2013; 19(4). DOI: 10.1007/s13365-013-0176-8
Source: PubMed


Despite the fact that the survival of people infected with human immunodeficiency virus (HIV) has improved worldwide because of the increasingly powerful and highly active antiretroviral therapy, opportunistic infections (OIs) of the central nervous system (CNS) remain a serious burden. HIV-1 is capable of entering the CNS through infected peripheral monocytes, but its effect on OIs of CNS remains unclear. In this study, we investigated the characteristics of HIV-1 in acquired immunodeficiency syndrome (AIDS) patients with CNS OIs. A total of 24 patients with CNS OIs and 16 non-CNS OIs (control) cases were selected. These AIDS patients were infected with HIV-1 by paid blood donors in China. HIV-1 loads in plasma and cerebrospinal fluid (CSF) were detected using RT-PCR, and the C2-V5 region of HIV-1 envelope gene was amplified from viral quasispecies isolated from CSF using nested PCR. The CSF HIV-1 load of CNS OIs was higher than that of non-CNS OIs, but plasma HIV-1 load of CNS OIs was not higher than that of non-CNS OIs. The nucleotide sequence of C2-V5 region of the HIV-1 quasispecies isolated from the CSF of CNS OIs had a high diversity, and the HIV-1 quasispecies isolated from the CSF of CNS OIs revealed R5 tropism as 11/25 charge rule. These results suggest that high levels of divergent HIV-1 quasispecies in the CNS probably contribute to opportunistic infections.

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    • "These findings suggest that the distinct CSF virus in the HAND patients represents a fitter viral variant found in the CNS and is advantageous for HIV-1 in a CNS infection. All viral quasispecies in the CNS of both clinical groups used the CCR5 coreceptor, while one HAND patient harbored R5X4/X4 viruses in the plasma; this observation is consistent with those of previous studies (Ohagen et al. 2003; Soulie et al. 2009; Zhang et al. 2013). Some studies have discovered an association between shorter AA length in certain regions of the env gene and neutralization sensitivity (Derdeyn et al. 2004; Rong et al. 2007). "
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    ABSTRACT: The genetic evolution of HIV-1 in the central nervous system (CNS) is different from that in peripheral tissues. We analyzed 121 clonal sequences of the V3-V5 regions of the env gene generated from paired cerebrospinal fluid (CSF) and plasma samples from nine chronically infected patients (four with HIV-associated neurocognitive disorder (HAND) and five without HAND). The sequence analysis indicated the significant differences between CSF and plasma was only observed in the C4 region (P = 0.043) in HAND patients. Significant increases in synonymous substitutions (dS) within the V4 region (P = 0.020) and in nonsynonymous substitutions (dN) within the C4 region (P = 0.029) were observed in the CSF-derived sequences. By contrast, CSF-derived sequences from non-HAND patients showed similar levels of diversity; dS and dN as the plasma-derived sequences. Signature differences between the CSF- and plasma-derived sequences were found at 12 amino acid positions for HAND patients and nine positions for non-HAND patients. Interestingly, five sites (positions 388, 396, 397, 404, and 406) that all belong to signature patterns exhibited positive selection pressure in CSF samples, but only site 406 was positively selected in the plasma samples from the HAND patients. Conversely, in the non-HAND patients, there were four sites (positions 397, 404, 432, and 446) showed positive selection pressure in the plasma samples, but only site 446 in the CSF samples. These results suggest that discordant patterns of genetic evolution occur between the tissue-specific HIV-1 quasispecies in the HAND and non-HAND patients. Viral molecular heterogeneity between specific tissues is greater in patients with HAND compared to non-HAND patients.
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    ABSTRACT: HIV-positive patients may be effectively treated with highly active antiretroviral therapy and such a strategy is associated with striking immune recovery and viral load reduction to very low levels. Despite undeniable results, the central nervous system (CNS) is commonly affected during the course of HIV infection, with neurocognitive disorders being as prevalent as 20-50 % of treated subjects. This review discusses the pathophysiology of CNS infection by HIV and the barriers to efficacious control of such a mechanism, including the available data on compartmental drug penetration and on pharmacokinetic/pharmacodynamic relationships. In the reviewed articles, a high variability in drug transfer to the CNS is highlighted with several mechanisms as well as methodological issues potentially influencing the observed results. Nevirapine and zidovudine showed the highest cerebrospinal fluid (CSF) to plasma ratios, although target concentrations are currently unknown for the CNS. The use of the composite CSF concentration effectiveness score has been associated with better virological outcomes (lower HIV RNA) but has been inconsistently associated with neurocognitive outcomes. These findings support the CNS effectiveness of commonly used highly antiretroviral therapies. The use of antiretroviral drugs with increased CSF penetration and/or effectiveness in treating or preventing neurocognitive disorders however needs to be assessed in well-designed prospective studies.
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