Host immunogenetic and inflammatory determinants of sensory neuropathy in HIV patients on antiretroviral therapy

[Truncated abstract] Since the introduction of Antiretroviral Therapy (ART), HIV-associated sensory neuropathy (HIV-SN) is recognized as the most common neurological complication in patients with HIV. Some develop neuropathy due to exposure to neurotoxic ART (NRTI-SN), but the pathogenesis remains unclear. The aim of this study is to elucidate the underlying inflammatory pathophysiology of HIV-SN (defined using the ACTG BPNS tool)* through clinical and basic research endeavours. To this end I used a three-tiered approach: 1. To determine if host TNF block haplotypes act as a predictor of SN risk, 51 Caucasian, 64 Malay, 72 Chinese and 339 South African HIV+ patients were genotyped for SNP within the TNFA gene and surrounding regions. The PHASE algorithm was used to statistically infer TNF block haplotypes and estimate their frequencies in each cohort. I established that TNF haplotypes FV6,7 associate independently with HIV-SN in Chinese, but not in Caucasian or South African patients. FV31 exhibited a protective effect against development of SN in the South African cohort. I showed that SNP associated with neuropathy do not affect neurocognitive change in Caucasian HIV+ patients stable on ART. This was associated with the FVa1,3,4, 12 haplotype family. 2. To investigate the effect of ART on circulating plasma chemokines and associate levels of plasma chemokines with NRTI-SN, plasma CXCL10, CCL2 and CXCL1 levels were measured in a cohort of 66 patients initiating ART in Malaysia with advanced immunodeficiency and many opportunistic infections. Plasma levels of CXCL10 decreased and CCL5 increased during ART. CCL2 levels were elevated by HIV disease, but did not change on ART. Some patients with SN displayed elevated levels of CCL5 on ART.