title: HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients.
abstract: The mechanism behind the selective depletion of CD4(+) cells in HIV infections remains undetermined. Although HIV selectively infects CD4(+) cells, the relatively few infected cells in vivo cannot account for the extent of CD4(+) T cell depletion, suggesting indirect or bystander mechanisms. The role of virus replication, Env glycoprotein phenotype, and immune activation (IA) in this bystander phenomenon remains controversial. Using samples derived from HIV-infected patients, we demonstrate that, although IA in both CD4(+) and CD8(+) subsets correlates with CD4 decline, apoptosis in CD4(+) and not CD8(+) cells is associated with disease progression. Because HIV-1 Env glycoprotein has been implicated in bystander apoptosis, we cloned full-length Envs from plasma of viremic patients and tested their apoptosis-inducing potential (AIP). Interestingly, AIP of HIV-1 Env glycoproteins were found to correlate inversely with CD4:CD8 ratios, suggesting a role of Env phenotype in disease progression. In vitro mitogenic stimulation of PBMCs resulted in upregulation of IA markers but failed to alter the CD4:CD8 ratio. However, coculture of normal PBMCs with Env-expressing cells resulted in selective CD4 loss that was significantly enhanced by IA. Our study demonstrates that AIP of HIV-1 Env and IA collectively determine CD4 loss in HIV infection.
authors.affiliation: Center of Excellence for Infectious Diseases, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905;
authors.forename: Anjali
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Center of Excellence for Infectious Diseases, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905;
authors.forename: Melina
authors.initials: M
authors.lastname: Sedano
authors.affiliation: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905;
authors.forename: Bethany
authors.initials: B
authors.lastname: Beauchamp
authors.affiliation: Center of Excellence for Infectious Diseases, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905;
authors.forename: Erin B
authors.initials: EB
authors.lastname: Punke
authors.affiliation: Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, El Paso, TX 79905; and.
authors.forename: Zuber D
authors.initials: ZD
authors.lastname: Mulla
authors.affiliation: Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905.
authors.forename: Armando
authors.initials: A
authors.lastname: Meza
authors.affiliation: Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905.
authors.forename: Ogechika K
authors.initials: OK
authors.lastname: Alozie
authors.affiliation: Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukherjee
authors.affiliation: Center of Excellence for Infectious Diseases, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905; himanshu.garg@ttuhsc.edu.
authors.forename: Himanshu
authors.identifier: http://orcid.org/0000-0001-8906-9300
authors.initials: H
authors.lastname: Garg
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015686:Gene Products, env / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008297:Male; D010641:Phenotype
chemical_list: D015686:Gene Products, env