Intrapatient alterations in the human immunodeficiency virus type 1 gp120 V1V2 and V3 regions differentially modulate coreceptor usage, virus inhibition by CC/CXC chemokines, soluble CD4, and the b12 and 2G12 monoclonal antibodies.
We studied human immunodeficiency virus type 1 (HIV-1) chimeric viruses altering in their gp120 V1V2 and V3 envelope regions to better map which genetic alterations are associated with specific virus phenotypes associated with HIV-1 disease progression. The V1V2 and V3 regions studied were based on viruses isolated from an individual with progressing HIV-1 disease. Higher V3 charges were linked with CXCR4 usage, but only when considered within a specific V1V2 and V3 N-linked glycosylation context. When the virus gained R5X4 dual tropism, irrespective of its V3 charge, it became highly resistant to inhibition by RANTES and highly sensitive to inhibition by SDF-1alpha. R5 viruses with higher positive V3 charges were more sensitive to inhibition by RANTES, while R5X4 dualtropic viruses with higher positive V3 charges were more resistant to inhibition by SDF-1alpha. Loss of the V3 N-linked glycosylation event rendered the virus more resistant to inhibition by SDF-1alpha. The same alterations in the V1V2 and V3 regions influenced the extent to which the viruses were neutralized with soluble CD4, as well as monoclonal antibodies b12 and 2G12, but not monoclonal antibody 2F5. These results further identify a complex set of alterations within the V1V2 and V3 regions of HIV-1 that can be selected in the host via alterations of coreceptor usage, CC/CXC chemokine inhibition, CD4 binding, and antibody neutralization.
Nabatov
Alexey A
AA
Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Pollakis
Georgios
G
Linnemann
Thomas
T
Kliphius
Aletta
A
Chalaby
Moustapha I M
MI
Paxton
William A
WA
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism; D018946:Chemokine CCL5 / Q000494:pharmacology; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000494:pharmacology; D019743:Chemokines, CXC / Q000494:pharmacology; D018450:Disease Progression; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics*; D015658:HIV Infections / Q000276:immunology* / Q000503:physiopathology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D009154:Mutation; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000235:genetics*; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012995:Solubility
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; C515255:CXCL12 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019713:Receptors, CCR5; D019718:Receptors, CXCR4