Tuberculous meningitis is associated with higher cerebrospinal HIV-1 viral loads compared to other HIV-1-associated meningitides.

To gain a better understanding of the immunopathogenesis of tuberculous meningitis (TBM) and identify potential diagnostic biomarkers that may discriminate TBM from other HIV-1-associated meningitides, we assessed HIV-1 viral load levels, drug resistance patterns in antiretroviral therapy (ART)-experienced patients with persistent viremia and soluble immunological analytes in peripheral blood and cerebrospinal fluid (CSF) of HIV-1 infected patients with TBM versus other meningitides. One hundred and three matched blood and CSF samples collected from HIV-1 infected patients with TBM or other meningitides presenting at a hospital in Durban, South Africa, from January 2009 to December 2011 were studied. HIV-1 RNA and 28 soluble immunological potential biomarkers were quantified in blood plasma and CSF. Viremic samples were assessed for HIV-1 drug resistance mutations. There were 16 TBM, 46 probable TBM, 35 non-TBM patients, and six unclassifiable patients. TBM and non-TBM patients did not differ in median plasma viral load but TBM patients had significantly higher median CSF viral load than non-TBM participants (p = 0.0005). No major drug resistance mutations were detected in viremic samples. Interleukin (IL)-1ß, IL-17, platelet derived growth factor (PDGF)-BB, granulocyte colony stimulating factor (G-CSF) and cathelicidin were significantly elevated in the CNS of TBM participants compared to other patients although these associations were lost after correction for false discovery. Our data suggest that TB co-infection of the CNS is associated with enhanced localized HIV-1 viral replication but none of the evaluated soluble immunological potential biomarkers could reliably distinguish TBM from other HIV-associated meningitides.

Gag drug resistance mutations in HIV-1 subtype C patients, failing a protease inhibitor inclusive treatment regimen, with detectable lopinavir levels.

The development of antiretroviral (ARV) drugs and their use in human immunodeficiency virus type 1 (HIV-1) has led to the effective control of HIV replication in infected patients. However the emergence of resistant HIV-1 strains still remains a problem. Literature has shown that mutations may accumulate in the protease (PR) and gag regions of HIV-1 patients who fail therapy with protease inhibitor (PI) drugs (1, 2). Gag mutations have also been found to play an important role in the evolution of PI resistance (2). Despite this, the standard genotypic drug-resistance test examines mutations in the reverse transcriptase (RT) and PR region of HIV-1 and not gag (3). This study investigated the frequency of gag drug resistance mutations in the absence of major PI mutations in HIV-1 subtype C patients, failing a PI inclusive treatment regimen. Sixty-eight samples were retrieved from patients that were classified as second line treatment failures as they had a viral load greater than 1000 copies\mL, as well as detectable lopinavir (LPV) levels. The gag and protease region of these patients were genotyped. Mutations in the gag and protease region were assessed using the REga Db sequencing tool and the CPR programme on the Stanford University HIV drug resistance database. The mean LPV level of these samples was 11.66 µg/mL. 69.11% (n=46) of the patients have no major PI mutations in protease. The following mutations that are associated with PI exposure were present in the data set: G62R (n=6), H219Q (n=11), S737T (n=8), I389T (n=8) and Q474L (n=7). Predictably, mutations that are associated with PI resistance were found, which are generally located in the p7/p1 and p1/p6 cleavage site. These mutations are K436R (n=4), I437V (n=1), L449P (n=5), R452K (n=4) and P453L\T (n=9). These results contribute to the knowledge of resistance mutations in gag and their impact on PI resistance.