Predominance of Detrimental Humoral Immune Responses to HIV‐1 in AIDS Patients with CD4 Lymphocyte Counts Less Than 400/mm³

Abstract

The humoral immune response to human immunodeficiency virus type 1 (HIV‐1) was studied in 25 AIDS patients with CD4 lymphocyte counts of less than 400/mm3. Humoral immune responses against tissue culture adapted strains of HIV‐1, and two limited‐passage patient isolates were investigated. Total anti‐HIV antibody levels were not significantly different between different individuals. Neutralizing titres against HIVLAI and HIVSF2 were 10‐ to 100‐fold higher than against clinical isolates. The complement‐mediated, antibody‐dependent enhancement of HIV‐1 infection titre was high (mean 1:14,000). Antibody‐complement mediated cytotoxicity of both HIVLAI and HIVSF2 was ineffective using human complement as a complement source. The antibody‐dependent, cell‐mediated cytotoxicity (ADCC) activity varied against the four isolates with tissue culture‐adapted strains being more susceptible than clinical isolates. Finally, an ADCC effector cell function, natural killer or NK activity, was measured for all 25 patients, and NK activity of patients was decreased by nearly 75% compared to uninfected individuals. In summary, beneficial humoral immune responses are low in HIV‐1 infected individuals with CD4 counts of less than 400/mm3 if the in vitro assay system is constructed to best mimic the in vivo situation. These results suggest that the lack of functional antibody responses to HIV may play an important role in viral pathogenesis.

Strong correlation between the complement-mediated antibody-dependent enhancement of HIV-1 infection and plasma viral load

“…Our present novel findings, together with those reported previously by our group and others [27][28][29], thus indicate that C-ADE may markedly influence the natural course of HIV disease. This assumption is in disagreement with the results of Montefiori et al [36], who did not find any correlation between C-ADEmediating antibodies and clinical progression.…”

“…We have measured C-ADE with a markedly higher frequency and in higher amounts in the sera of patients with advanced stage HIV disease compared with those in the sera of asymptomatic HIV-infected persons [27]. These findings were recently confirmed by McDougall et al [28]. In a more recent study [29], we have demonstrated the appearance of high-titre C-ADE to predict the rapid decline of the CD4 cell counts and an increased probability of the development of AIDS.…”

Comparison of Human Immunodeficiency Virus (HIV)-Specific Infection-Enhancing and -Inhibiting Antibodies in AIDS Patients

“…Similarly, neutralizing MAbs do not mediate infection enhancement and vice versa (44). Complement alone or in the presence of antibodies, however, may cause increased levels of adhesion of the virions to target cells via complement receptors and may thus abrogate the neutralizing effect of sera, as reported here and by McDougall et al (25). It is noteworthy that epitopes for the IEAs have been mapped to the N-terminal two-thirds of the extracellular part of gp41 (36), whereas the NAs recognize epitopes mainly in the variable and CD4 binding domains of the viral envelope proteins of HIV-1 (13, 33a, 34, 35, 39).…”

Stoichiometry of Envelope Glycoprotein Trimers in the Entry of Human Immunodeficiency Virus Type 1

“…Furthermore, when the T value is 1, many of the Env spikes on a virion are dispensable for infectivity, allowing a high level of defectiveness. Functionally defective HIV-1 Env proteins, including shed gp120 and the gp41 remnants of subunit dissociation, have been suggested to act as decoy antigens that promote nonneutralizing antibody responses (57,69,87). Low requirements for viral glycoproteins on the retrovirus surface allow the envelope to be densely populated with cellular adhesion molecules, which can facilitate virus-cell attachment in a process that is invisible to the host immune system (34,71,93,98).…”