The gp120 protein is a second determinant of decreased neurovirulence of Indian HIV-1C isolates compared to southern African HIV-1C isolates.

Vasudev R Rao,Eliseo Eugenin,Vinayaka R Prasad,Ujjwal Neogi,Ashok Chauhan

doi:10.1371/journal.pone.0107074

Vasudev R Rao, Eliseo Eugenin + Show 3 more

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https://doi.org/10.1371/journal.pone.0107074

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Abstract

Regional differences in neurovirulence have been documented among subtype/clade-C HIV-1 isolates in India and Southern Africa. We previously demonstrated that a C31S substitution in Clade-C Tat dicysteine motif reduces monocyte recruitment, cytokine induction and direct neurotoxicity. Therefore, this polymorphism is considered to be a causative factor for these differences in neurovirulence. We previously reported on the genotypic differences in Tat protein between clade-C and rest of the clades showing that approximately 90% of clade-C HIV-1 Tat sequences worldwide contained this C31S polymorphism, while 99% of non-clade C isolates lacked this Tat polymorphism at C31 residue (Ranga et al. (2004) J Virol 78∶2586–2590). Subsequently, we documented intra-clade-C differences in the frequency of Tat dicysteine variants between India and Southern Africa, as the basis for differential disease severity and showed the importance of the Tat dicysteine motif for neuropathogenesis using small animal models. We have now examined if determinants of neurovirulence besides Tat are different between the clade-C HIV-1 isolates from Southern Africa and India. Envelope glycoprotein gp120 is a well-documented contributor to neurotoxicity. We found that gp120 sequences of HIV-1 isolates from these two regions are genetically distinct. In order to delineate the contribution of gp120 to neurovirulence, we compared direct in vitro neurotoxicity of HIV-infected supernatants of a representative neurovirulent US clade-B isolate with two isolates each from Southern Africa and India using primary human neurons and SH-SY5Y neuroblastoma cells. Immunodepletion of gp120 of both US clade B and the Southern African clade C isolates revealed robust decreases in neurotoxicity, while that of the Indian isolates showed minimal effect on neurotoxicity. The gp120 as a cause of differential neurotoxicity was further confirmed using purified recombinant gp120 from HIV isolates from these regions. We conclude that gp120 is one of the key factors responsible for the decreased neurovirulence of Indian clade C HIV-1 isolates when compared to South African clade C HIV-1.

Highlights

HIV associated neurocognitive disorders (HAND) represent a spectrum of neurological disorders ranging from the mild asymptomatic neurocognitive impairment (ANI), the intermediate mild neurocognitive disorder (MND) to the severe HIV associated dementia (HAD)
We found that the low incidence of HAD in India correlates with the low percentage (1–2%) of isolates with Tat-CC motif in India and Bangladesh, while the higher incidence of HAND in Southern African countries correlates with a higher percentage (20–26%) of Tat-CC isolates in South Africa, Botswana and Zambia [18]
We showed that the Tat protein from the Southern African HIV-1 isolate displayed robust in vitro neurotoxicity, while that of Indian HIV-1C was minimal [18] suggesting that differences in Tat dicysteine motif played a key role in the intra-clade, differential neurovirulence

Summary

Introduction

HIV associated neurocognitive disorders (HAND) represent a spectrum of neurological disorders ranging from the mild asymptomatic neurocognitive impairment (ANI), the intermediate mild neurocognitive disorder (MND) to the severe HIV associated dementia (HAD). We found that the low incidence of HAD in India correlates with the low percentage (1–2%) of isolates with Tat-CC motif in India and Bangladesh, while the higher incidence of HAND in Southern African countries correlates with a higher percentage (20–26%) of Tat-CC isolates in South Africa, Botswana and Zambia [18] These studies indicated that clade C predominates in both India and Southern African countries, there are intra-clade Tat genetic differences that can lead to different clinical outcomes and emphasizes the need for a closer look at polymorphisms in key viral neurotoxic genes when comparing neurocognitive differences. We showed that the Tat protein from the Southern African HIV-1 isolate displayed robust in vitro neurotoxicity, while that of Indian HIV-1C was minimal [18] suggesting that differences in Tat dicysteine motif played a key role in the intra-clade, differential neurovirulence

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