A role for antibodies in natural HIV control

Abstract

Purpose of the review Rare patients naturally control HIV replication without antiretroviral therapy. Understanding the mechanisms implicated in natural HIV control will inform the development of immunotherapies against HIV. Elite controllers (EC) are known for developing efficient antiviral T cell responses, but recent findings suggest that antibody (Ab) responses also play a significant role in HIV control. We review the key studies that uncovered a potent memory B cell response and highly functional anti-HIV Ab in EC, and explore the mechanisms that may account for the distinct properties of their humoral response. Recent findings EC maintain a large HIV-specific memory B cell pool that is sustained by efficient Tfh function. Neutralizing Ab rarely show high titers in controllers, but seem capable, at least in certain cases, of neutralizing contemporaneous viral strains. In addition, EC display a unique HIV-specific Ab profile in terms of isotype, antigen specificity, and glycosylation pattern, resulting in polyfunctional Ab effector functions that may promote infected cell lysis and prime effectors of the antiviral immune response.

Update on Fc-Mediated Antibody Functions Against HIV-1 Beyond Neutralization

“…Antibodies have now been proven to contribute to HIV protection and are therefore a central component of new vaccine strategies (189). As Fc-FcR interactions are able to generate powerful extraneutralizing Fc functions, these additional functions should be defined (159).…”

Transient viral exposure drives functionally-coordinated humoral immune responses in HIV-1 post-treatment controllers

“…However, as opposed to spontaneous controllers, PTC neither frequently carry the protective HLA class I alleles (i.e., HLA-B*57 and HLA-B*27), nor possess highly efficient cytotoxic CD8 + T lymphocytes 10 – 12 . Coordinated and functional antibody B-cell responses often develop in natural HIV-1 controllers 13 . In fact, elite controllers who are characterized by suppressed viremia conserve high frequencies of circulating follicular helper T (cTfh) cells, and HIV-1-specific memory B cells 14 , 15 , and produce polyfunctional antibodies equipped with cross-neutralizing and Fc-dependent effector activities 16 – 21 .…”

“…Sustained viral antigenic stimulation and diversification in very low viremia settings such as in natural controllers can thus support the development of broadly neutralizing antibodies (bNAbs) targeting the HIV-1 surface envelope glycoprotein (Env) 22 . Hence, a potential role of humoral immunity in the slow progression and natural control of HIV-1 infection has been proposed 13 . Early ART also preserves blood and gut HIV-1-specific B cells 5 , 23 , 24 , but precludes the formation of potent or cross-neutralizing antibody responses upon treatment-induced viral suppression 25 .…”

Discordance between the predicted vs. the actually recognized CD8+ T cell epitopes of HCMV pp65 antigen and aleatory epitope dominance

“…There is an increasing number of conditions, however, in which serum antibodies fail to reveal even the immune status of an individual. These include tuberculosis 1 , Lyme disease 2 , human immunodeficiency virus (HIV) elite controllers 3 , up to 30% of human cytomegalovirus (HCMV) infected individuals 4 , and SARS-CoV-2 infection: in the latter, as with other human coronavirus infections, only a transient antibody response tends to occur, after which specific serum antibodies decline to below detection limit 5 . In all the aforementioned conditions, however, antigen-specific T cell immunity could be detected (see the corresponding references above), verifying that an in immune response had indeed occurred, suggesting that cell-mediated immunity can occur, and render protection, in the absence of detectable humoral immunity.…”