HIV-1C env and gag Variation in the Cerebrospinal Fluid and Plasma of Patients with HIV-Associated Cryptococcal Meningitis in Botswana.

Nametso Kelentse,Kwana Lechiile,Tshepo B Leeme,Natasha O Moraka,Thomas S Harrison,Rosemary Musonda,Sikhulile Moyo,Mompati L Mogwele,Simani Gaseitsiwe,Doreen Ditshwanelo,Baitshepi Mokaleng,David S Lawrence,Ishmael Kasvosve,Joseph N Jarvis

doi:10.3390/v12121404

Abstract

HIV-1 compartmentalization in reservoir sites remains a barrier to complete HIV eradication. It is unclear whether there is variation in HIV-1 env and gag between cerebrospinal fluid (CSF) and plasma of individuals with HIV-associated cryptococcal meningitis (CM). We compared HIV-1 env characteristics and the gag cytotoxic T-lymphocyte (CTL) escape mutations from CSF and plasma samples. Employing population-based Sanger sequencing, we sequenced HIV-1 env from CSF of 25 patients and plasma of 26 patients. For gag, 15 CSF and 21 plasma samples were successfully sequenced. Of these, 18 and 9 were paired env and gag CSF/plasma samples, respectively. There was no statistically significant difference in the proportion of CCR5-using strains in the CSF and plasma, (p = 0.50). Discordant CSF/plasma virus co-receptor use was found in 2/18 pairs (11.1%). The polymorphisms in the HIV-1 V3 loop were concordant between the two compartments. From the HIV-1 gag sequences, three pairs had discordant CTL escape mutations in three different epitopes of the nine analyzed. These findings suggest little variation in the HIV-1 env between plasma and CSF and that the CCR5-using strains predominate in both compartments. HIV-1 gag CTL escape mutations also displayed little variation in CSF and plasma suggesting similar CTL selective pressure.

Highlights

In the course of infection, the human immunodeficiency virus (HIV) can cross the blood-brain-barrier and infect the central nervous system (CNS) [1,2]
Previous studies have shown that inflammation of the meninges caused by cryptococcal meningitis (CM) may result in the disruption of the blood-brain barrier (BBB), thereby causing the HIV-infected cells to penetrate the barrier into the CNS [7,8]
We had initially hypothesized that many of these isolates would be CXCR4-using strains since the participants are at an advanced stage of HIV infection as shown by the presence of CM and low CD4+ T-cell count; a high number of CCR5-using strains were observed in both compartments with no statistically significant difference in the proportion of CCR5-using strains in plasma and cerebrospinal fluid (CSF) (p = 0.5)

Summary

Introduction

In the course of infection, the human immunodeficiency virus (HIV) can cross the blood-brain-barrier and infect the central nervous system (CNS) [1,2]. Early after HIV infection can reduce viral diversity significantly, compartmentalized quasispecies are still observed in the CNS [4]. Variation in viral diversity in the CNS and peripheral blood has potentially important implications for HIV drug treatment and vaccine development and is considered to be a key barrier to successful HIV eradication [5]. Previous studies have shown that inflammation of the meninges caused by CM may result in the disruption of the blood-brain barrier (BBB), thereby causing the HIV-infected cells to penetrate the barrier into the CNS [7,8]. Once in the CNS, the virus may be subjected to different immune and/or drug pressure; whether or not the CNS quasispecies is distinct from those from peripheral blood is still not confirmed

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Conclusion