Journal of Dementia
Open Access

HAND; HIV; V3 and C3 regions; env sequences; neurotoxicity in HIV patients

HIV-associated neurocognitive disorder is now acknowledged as a cause of morbidity and mortality among HIV-infected individuals [1]. Mostly, it occurs when CD4+ lymphocyte counts fall below 200 cells/ mL and late stages of acquired immunodeficiency syndrome (AIDS) [2]. Nearly 50% patients manifest the symptoms of HAND prior to their deaths [3]. The prevalence of HAND in adult people ranges from 19% to 52% in developed country [4-5], and 14% to 64% in developing countries [6-7]. In India, the prevalence of HAND patients is ~ 32.50% [8].

The multifactorial disease like HAND is influenced by continuous immune activation and central nervous system (CNS) inflammation [9]. The development of HAND is influenced by many other factors like host and HIV-related which speed up the progression of HAND [10-13]. HAND and the neurotoxicity is result of synchronised actions of trans-activating protein (Tat) and envelope glycoprotein (Env) [14]. It was reported that gp120 fragment of Env protein could mediate neuronal damage in brain tissue [15-17]. The genotypic and phenotypic diversity of HIV is influenced by hypervariable region 3 (V3) of gp120 fragment. The viral phenotypes and cell tropism are influenced by the interaction of V3 (V3 loop) with chemokine co receptors CCR5 or CXCR4 [18]. The persistent replication of virus in the CNS has been associated with CCR5 tropism, macrophage/microglia tropism [19-21]. The viral diversity in the CNS resulted from the inability of serum to neutralize recombinant virus containing C2V3 regions [22]. Evidence indicates, variation in V3 region influences CNS toxicity [23-24]. A study reported significant genetic differences for constant region 4 (C4 region) while compared in the samples of CSF and plasma between patients with and without HAND [25]. The amino acid composition and PNLGs spanning of C4 to V5 have a roles in antibody evasion [26] and enhanced viral infectivity [27-28, 25].

Hence, diversity in env gene sequence of CNS may provide persistence of higher virus infection in the CNS. Till now, the exact time of advancement of env in the CNS is not known. Although studies suggested that appearance of diverse viral population consequences before the manifestation of neuropath logical condition [29-31]. The evolutionary patterns of viral isolates in tissues vary between patients with or without HAND [32, 25]. In HAND patients, a higher rate of genetic evolution was observed in the lymphoid tissues [25]. A study reported a higher viral diversity in patients with HAD than without HAD [22].

Worldwide, ∼50% of the HIV infection is associated with the subtype C (Esparza et al., 2000). It is rapidly growing epidemics in Asia and sub-Saharan Africa including China and India [33]. In addition to that the progression of HIV infection is influenced by virus subtype, genetic, demographic factors [34-35]. The molecular and biological properties of subtype C vary from other subtypes. Till now, report has not been published whether these differences explain to differential pathogenic properties [36]. Hence we comprehended the genetic profile of the gp120 protein of HIV-1 env gene which influences the pathogenesis of neurocognitive diseases

Method

We led the search utilizing multiple databases, specifically, EMBASE, PubMed (Medline), and Google Scholar. We have done the literature survey on HIV-1 env gene sequence.

Discussion

Mostly neurotoxicity is determined by cysteine-rich motifs of Tat in clade C isolates. In addition to that, variability in neurotoxicity is influenced by genetic differences in gp120 of clade C [37]. In Tat sequence analysis, it was reported that there are six amino acid residues which are differentially conserved in subtype C Tat (C-Tat). Out of that, more than 90% are subtype C viruses encoded a serine and >99% are conserved in non-subtype C viruses encoded a cysteine (at position 31) [38]. In addition to that, the neurotoxicity is influenced by clade-specific variations [39]. It was reported that HIV clade C strains of India is less neurotoxic than clade C strain from southern Africa [39]. Individuals with clade B HIV-1 infection are more susceptible to neurotoxicity than clade C [40]. However, none of the study described the mechanism of neurotoxicity in astrocytes [41]. The mediators of neurotoxicity are present in the V3 and C3 regions of gp120 motifs. Variation in env sequence not only affects the cell entry and neurotropism but also affects the neurotoxicity. Though, the specific factors which contribute to development of neurotropic and neurovirulent is not well defined.

Summary

Pathogenesis of HAND is influenced by HIV-1 env sequences. The gp120 glycoprotein serves as a factor to cross the blood-brain barrier and conserve neurocognitive impairments. The variation in env gene sequences in the CNS leads to neurotoxic and neurovirulent features.

Future

Further analysis of the HIV-1 env gene sequence in larger number of HAND patients will address the genetic variations of gp120 protein of HIV-1 env. Comparative studies on genetic profiling of V3 and C3 regions of gp120 motifs among HAND patients of different ethnic region will provide correlation between V3 and C3 regions and IHDS and cognition parameters.

Comparative studies on genetic profile of V3 and C3 regions of gp120 protein will be helpful to address the pathogenesis of HAND patients. Correlation of genetic profile of V3 and C3 regions of gp120 motifs with International HIV Dementia Scale (IHDS) and cognition parameters (attention, memory, language, reaction time, and perception) will provide viral marker for the development of HAND

Acknowledgments

We gratefully acknowledge the ICMR-National AIDS Research Institute for providing environment.

Ethical approval: Not required

Conflict of interest: The authors declare that there is no conflict of interests

Competing interests: The author declares that there are no competing interests

Source of funding: Nil

Authors Contribution:

HariOm Singh: Writing & review

Amita Singh: Writing of manuscript

Vivek Gupta: Review of Manuscript

1. R Mohamed AA, Oduor C, Kinyanjui D( 2020) HIV-Associated Neurocognitive Disorders at Moi Teaching and Referral Hospital, Eldoret, Kenya. BMC Neurol 20:280

Indexed at, Google Scholar, Crossref

2. Ances BM; Ellis RJ (2007) Demena and Neurocognitive Disorders Due to HIV-1 Infection. Semin Neurol 27:86-92.

Indexed at, Google Scholar, Crossref

3. Alford K, Vera JH. (2018)Cognitive Impairment in People Living with HIV in The ART Era: A Review. Br Med Bull 127:55-68. 

Indexed at, Google Scholar, Crossref

4. Kelly Cm, Van Oosterhout Jj, Ngwalo C, Stewart Rc, Benjamin L, et al.( 2014)Hiv       Associated   Neurocognitive Disorders (Hand) In Malawian Adults And Effect on Adherence to Combination Anti-Retroviral Therapy: A Cross Sectional Study. Plos one 9:E98962.

Indexed at, Google Scholar, Crossref

5. Van Wijk C. (2013) Screening for Hiv-Associated Neurocognitive Disorders (Hands) in South Africa: A Caution Against Uncritical use of Comparative Data from other Developing Countries. S Afr J Hiv Med 14: 17-19

Indexed at, Google Scholar, Crossref

6. Atashili J, Gaynes Bn, Pence Bw, Tayong G, Kats D, et al.( 2013 ) Characteristics and Correlates of A Positive-Dementia Screen In Patients on Antiretroviral Therapy in Bamenda, Cameroon: A Cross-Sectional Study. Bmc Neurol 13:86.

Indexed at, Google Scholar, Crossref

7. Lawler K, Mosepele M, Ratcliffe S, Seloilwe E, Steele K, et al.(2010) Neurocognitive Impairment among Hiv-Positive Individuals in Botswana: A Pilot Study. J Int Aids Soc 13:15

Indexed at, Google Scholar, Crossref

8. Saini S , Barar V K.( 2016) Impact of Hiv Associated Neurocognitive Disorders on Activities of Daily Living and Its Association with Depression in Outdoor Patients Undergoing Haart. J Young Pharm 8: 279-283

Indexed at, Google Scholar, Crossref

9. Spudich S, González-Scarano F.( 2012) Hiv-1-Related Central Nervous System Disease: Current issues in Pathogenesis, Diagnosis, and Treatment. Cold Spring Harb Perspect Med 2:A007120.

Indexed at, Google Scholar, Crossref

10. Heaton Rk, Clifford Db, Franklin Dr Jr, Woods Sp, Ake C, et al. (2010) Charter Group. Hiv-Associated Neurocognitive Disorders Persist in The Era of Potent Antiretroviral Therapy: Charter Study. Neurol 75:2087-2096

Indexed at, Google Scholar, Crossref

11. Robertson Kr, Smurzynski M, Parsons Td, Wu K, Bosch Rj, et al. (2007) The Prevalence and Incidence of Neurocognitive Impairment In The Haart Era. Aids. 21:1915-1921.

Indexed at, Google Scholar, Crossref

12. Tozzi V, Balestra P, Lorenzini P, Bellagamba R, Galgani S, et al. (2005) Prevalence and Risk Factors for Human Immunodeficiency Virus-Associated Neurocognitive Impairment, 1996 To 2002: Results from an Urban Observational Cohort. J Neurovirol 11:265-273. 

Indexed at, Google Scholar, Crossref

13. Purohit V, Rapaka R, Shurtleff D.( 2011) Drugs of Abuse, Dopamine, and Hiv-Associated Neurocognitive Disorders/Hiv-Associated Dementia. Mol Neurobiol 44:102-110.

Indexed at, Google Scholar, Crossref

14. Toggas Sm, Masliah E, Rockenstein Em, Rall Gf, Abraham Cr, et al.( 1994) Central Nervous System Damage Produced by Expression of The Hiv-1 Coat Protein Gp120 in Transgenic Mice. Nature 367:188-193

Indexed at, Google Scholar, Crossref

15. Jana A, Pahan K. (2004) Human Immunodeficiency Virus Type 1 Gp120 Induces Apoptosis in Human Primary Neurons Through Redox-Regulated Activation of Neutral Sphingomyelinase. J Neurosci 24:9531-9540.

Indexed at, Google Scholar, Crossref

16. Zhang K, Rana F, Silva C, Ethier J, Wehrly K, Et Al.( 2003) Human Immunodeficiency Virus Type 1 Envelope-Mediated Neuronal Death: Uncoupling of Viral Replication and Neurotoxicity. J Virol 77:6899-6912.

 Indexed at, Google Scholar, Crossref

17. Bachis A, Cruz Mi, Mocchetti I.( 2010) M-Tropic Hiv Envelope Protein Gp120 Exhibits A Different Neuropathological Profile than T-Tropic Gp120 in Rat Striatum. Eur J Neurosci 32:570-578.

Indexed at, Google Scholar, Crossref

18. Hartley O, Klasse Pj, Sattentau Qj, Moore Jp.( 2005 ) V3: Hiv's Switch-Hitter. Aids Res Hum Retrovir 21:171-189.

  Indexed at, Google Scholar, Crossref

19. Rossi F, Querido B, Nimmagadda M, Cocklin S, Navas-Martín S, et al.( 2008) The V1-V3 Region of A Brain-Derived Hiv-1 Envelope Glycoprotein Determines Macrophage Tropism, Low Cd4 Dependence, Increased Fusogenicity and Altered Sensitivity to Entry Inhibitors. Retrovirol 5:89. 

Indexed at, Google Scholar, Crossref

20. Albright Av, Shieh Jt, Itoh T, Lee B, Pleasure D, et al.( 1999 ) Microglia Express Ccr5, Cxcr4, And Ccr3, But of These, Ccr5 Is The Principal Coreceptor for Human Immunodeficiency Virus Type 1 Dementia Isolates. J Virol 73:205-213.

Indexed at, Google Scholar, Crossref

21. Gorry Pr, Taylor J, Holm Gh, Mehle A, Morgan T, et al.( 2002) Increased Ccr5 Affinity and Reduced Ccr5/Cd4 Dependence of A Neurovirulent Primary Human Immunodeficiency Virus Type 1 isolate. J Virol 76:6277-6292.

                 Indexed at, Google Scholar, Crossref

22. Van Marle G, Rourke Sb, Zhang K, Silva C, Ethier J, et al.(2002). Hiv Dementia Patients Exhibit Reduced Viral Neutralization and Increased Envelope Sequence Diversity in Blood and Brain. Aids 16:1905-1914.

                    Indexed at, Google Scholar, Crossref

23. Thompson Ka, Churchill Mj, Gorry Pr, Sterjovski J, Oelrichs Rb, et al. (2004)Astrocyte Specific Viral Strains in Hiv Dementia. Ann Neurol 56:873-877.

               Indexed at, Google Scholar, Crossref

24. Dunfee Rl, Thomas Er, Wang J, Kunstman K, Wolinsky Sm, et al.( 2007) Loss of The N-Linked Glycosylation Site at Position 386 In The Hiv Envelope V4 Region Enhances Macrophage Tropism and is Associated with Dementia. Virol 367:222-234.

                 Indexed at, Google Scholar, Crossref

25. Ouyang Y, Liu L, Zhang Y, Yuan L, Liu Z, et al.(2014) Discordant Patterns of Tissue-Specific Genetic Characteristics in The Hiv-1 Env Gene From Hiv-Associated Neurocognitive Disorder (Hand) and Non-Hand Patients. J Neurovirol 20:332-340. 

                 Indexed at, Google Scholar, Crossref

26. Wang W, Nie J, Prochnow C, Truong C, Jia Z, Et al.( 2013) A Systematic Study of The N-Glycosylation Sites of Hiv-1 Envelope Protein on Infectivity and Antibody-Mediated Neutralization. Retrovirol 10:14.

              Indexed at, Google Scholar, Crossref

27. Dunfee Rl, Thomas Er, Gorry Pr, Wang J, Taylor J, et al. (2006)The Hiv Env Variant N283 Enhances Macrophage Tropism and is Associated With Brain Infection and Dementia. Proc Natl Acad Sci U S A. 103:15160-15165.

                Indexed at, Google Scholar, Crossref

28. Dunfee Rl, Thomas Er, Gabuzda D (2009) Enhanced Macrophage Tropism of HIV in Brain and Lymphoid Tissues is Associated with Sensitivity to the Broadly Neutralizing Cd4 Binding Site Antibody B12. Retrovirol 6:69.

                 Indexed at, Google Scholar, Crossref

29. McCrossan M, Marsden M, Carnie FW, Minnis S, Hansoti B, et al. (2006) An Immune Control Model for Viral Replication in the CNS during Presymptomatic HIV Infection. Brain 129: 503-516.

              Indexed at, Google Scholar, Crossref

30. Smit TK, Wang B, Ng T, Osborne R, Brew B, et al. (2001) Varied Tropism of HIV-1 Isolates Derived From Different Regions of Adult Brain Cortex Discriminate Between Patients with and Without AIDS Dementia Complex (ADC): Evidence for Neurotropic HIV Variants. Virol 27: 509-526.

                Indexed at, Google Scholar, Crossref

31. Chen MF, Westmoreland S, Ryzhova EV, Martin-Garcia J, Soldan SS, et al. (2006) Simian Immunodeficiency Virus Envelope Compartmentalizes In Brain Regions Independent of Neuropathology. J Neurovirol 1:73-89.

               Indexed at, Google Scholar, Crossref

32. Lamers SL, Salemi M, Galligan DC, Morris A, Gray R, et al. (2010) Human Immunodeficiency Virus-1 Evolutionary Patterns Associated with Pathogenic Processes in the Brain. J Neurovirol 16:230-241.

Indexed at, Google Scholar, Crossref

33. Esparza J, Bhamarapravati N (2000) Accelerating the Development and Future Availability of HIV-1 Vaccines: Why, When, Where, and How?. Lancet 355:2061-2066.

                Indexed at, Google Scholar, Crossref

34. Essex M (1999) Human Immunodeficiency Viruses in the Developing World. Adv Virus Res 53:71-88.

               Indexed at, Google Scholar, Crossref

35. Peeters M, Sharp PM (2000) Genetic Diversity of HIV-1: The Moving Target. AIDS 14:S129-S140.

             Indexed at, Google Scholar, Crossref

36. Hu DJ, Buvé A, Baggs J, van der Groen G, Dondero TJ (1999) What Role Does HIV-1 Subtype Play in Transmission and Pathogenesis? An Epidemiological Perspective. AIDS 13:873-881.

              Indexed at, Google Scholar, Crossref

37. Everall I, Vaida F, Khanlou N, Lazzaretto D, Achim C, et al. (2009) Cliniconeuropathologic Correlates of Human Immunodeficiency Virus in the Era of Antiretroviral Therapy. J Neurovirol 15:360-370.

              Indexed at, Google Scholar, Crossref

38. Ranga U, Shankarappa R, Siddappa NB, Ramakrishna L, Nagendran R, et al. (2004) Tat Protein of Human Immunodeficiency Virus Type 1 Subtype C Strains Is a Defective Chemokine. J Virol 78:2586-2590.

                 Indexed at, Google Scholar, Crossref

39. Rao VR, Neogi U, Talboom JS, Padilla L, Rahman M, et al. (2013) Clade C HIV-1 Isolates Circulating In Southern Africa Exhibit A Greater Frequency of Dicysteine Motif-Containing Tat Variants Than Those In Southeast Asia and Cause Increased Neurovirulence. Retrovirol 10:61.

              Indexed at, Google Scholar, Crossref

40. Constantino AA, Huang Y, Zhang H, Wood C, Zheng JC. (2011) HIV-1 Clade B and C Isolates Exhibit Differential Replication: Relevance to Macrophage-Mediated Neurotoxicity. Neurotox Res 20:277-288.

               Indexed at, Google Scholar, Crossref

41. Samikkannu T, Agudelo M, Gandhi N, Reddy PV, Saiyed ZM, et al. (2011) Human Immunodeficiency Virus Type 1 Clade B and C Gp120 Differentially Induce Neurotoxin Arachidonic Acid in Human Astrocytes: Implications For Neuroaids. J Neurovirol 17(3):230-238.

             Indexed at, Google Scholar, Crossref