Viremic HIV infected individuals with high CD4 T cells and functional envelope proteins show anti-gp41 antibodies with unique specificity and function.
BACKGROUND
CD4 T-cell decay is variable among HIV-infected individuals. In exceptional cases, CD4 T-cell counts remain stable despite high plasma viremia. HIV envelope glycoprotein (Env) properties, namely tropism, fusion or the ability to induce the NK ligand NKp44L, or host factors that modulate Env cytopathic mechanisms may be modified in such situation.


METHODS
We identified untreated HIV-infected individuals showing non-cytopathic replication (VL>10,000 copies/mL and CD4 T-cell decay<50 cells/µL/year, Viremic Non Progressors, VNP) or rapid progression (CD4 T-cells<350 cells/µL within three years post-infection, RP). We isolated full-length Env clones and analyzed their functions (tropism, fusion activity and capacity to induce NKp44L expression on CD4 cells). Anti-Env humoral responses were also analyzed.


RESULTS
Env clones isolated from VNP or RP individuals showed no major phenotypic differences. The percentage of functional clones was similar in both groups. All clones tested were CCR5-tropic and showed comparable expression and fusogenic activity. Moreover, no differences were observed in their capacity to induce NKp44L expression on CD4 T cells from healthy donors through the 3S epitope of gp41. In contrast, anti- Env antibodies showed clear functional differences: plasma from VNPs had significantly higher capacity than RPs to block NKp44L induction by autologous viruses. Consistently, CD4 T-cells isolated from VNPs showed undetectable NKp44L expression and specific antibodies against a variable region flanking the highly conserved 3S epitope were identified in plasma samples from these patients. Conversely, despite continuous antigen stimulation, VNPs were unable to mount a broad neutralizing response against HIV.


CONCLUSIONS
Env functions (fusion and induction of NKp44L) were similar in viremic patients with slow or rapid progression to AIDS. However, differences in humoral responses against gp41 epitopes nearby 3S sequence may contribute to the lack of CD4 T cell decay in VNPs by blocking the induction of NKp44L by gp41.
IrsiCaixa-HIVACAT, Institut de Recerca en Ciències de la Salut Germans Trias i Pujol (IGTP), Hospital Germans Trias, Universitat Autònoma de Barcelona, Badalona, Barcelona, Catalonia, Spain.
Marta
M
Curriu
Hughes
H
Fausther-Bovendo
María
M
Pernas
Marta
M
Massanella
Jorge
J
Carrillo
Cecilia
C
Cabrera
Cecilio
C
López-Galíndez
Bonaventura
B
Clotet
Patrice
P
Debré
Vincent
V
Vieillard
Julià
J
Blanco
D000595:Amino Acid Sequence; D000918:Antibody Specificity; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D056724:Immunity, Humoral; D008969:Molecular Sequence Data; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000378:metabolism; D013997:Time Factors; D056189:Viral Tropism / Q000276:immunology; D014766:Viremia / Q000276:immunology* / Q000378:metabolism; D053586:Virus Internalization
D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D055629:Natural Cytotoxicity Triggering Receptor 2