Humoral immunity to HIV‐1: neutralization and beyond

Abstract

Humoral immunity is considered a key component of effective vaccines against HIV-1. Hence, an enormous effort has been put into investigating the neutralizing antibody response to HIV-1 over the past 20 years which generated key information on epitope specificity, potency, breadth and in vivo activity of the neutralizing antibodies. Less clear is still the role of antibody-mediated effector functions (antibodydependent cellular cytotoxicity, phagocytosis, complement system) and uncertainty prevails whether Fc-mediated mechanisms are largely beneficial or detrimental for the host. The current knowledge on the manifold functions of the humoral immune response in HIV infection, their underlying mechanisms and potential in vaccine-induced immunity will be discussed in this review.

The good and evil of complement activation in HIV-1 infection

“…The majority of nAbs neutralize free virions by preventing receptor engagement, an essential step in the life cycle of all Env viruses, or by interfering with the fusion process. 34 Later in the viral life cycle, nAbs that block replication by preventing viral uncoating or budding have been described in several viral diseases. 34 The HIV-1-specific nAbs described to date interfere with viral attachment to the cellular receptor CD4, binding to the coreceptor (most commonly CCR5 or CXCR4), or postreceptor engagement in the actual fusion process.…”

“…34 Later in the viral life cycle, nAbs that block replication by preventing viral uncoating or budding have been described in several viral diseases. 34 The HIV-1-specific nAbs described to date interfere with viral attachment to the cellular receptor CD4, binding to the coreceptor (most commonly CCR5 or CXCR4), or postreceptor engagement in the actual fusion process. [35][36][37][38][39][40][41][42][43][44][45] When a host is infected with a virus, Abs are produced against many epitopes on multiple viral proteins.…”

“…[35][36][37][38][39][40][41][42][43][44][45] When a host is infected with a virus, Abs are produced against many epitopes on multiple viral proteins. These Abs consist of a mixture of nAbs and non-nAbs, which can contribute to antiviral immunity in four ways: 34 (i) nAbs directly neutralize free virus particles; (ii) both nAbs and non-nAbs trigger complement-mediated lysis of free virus particles and infected cells via specific Ab-antigen binding events and complement activation; (iii) both nAbs and non-nAbs bind to and coat viruses to mediate opsonization and phagocytosis by macrophages and other cells; and (iv) both nAbs and non-nAbs trigger destruction of viruses by stimulating other immune responses such as Ab-dependent cellular cytotoxicity (ADCC).…”

“…34,46 Within a few weeks of infection, Abs against the viral Env (gp120 and gp41), core (Gag) and matrix (p17) become detectable in the plasma of HIV-1-positive individuals. [47][48][49][50][51][52] Ab levels mount in response to the gradual increase in viral load and appear to be maintained at high levels throughout the disease.…”

“…It is currently believed that only a fraction of the elicited Abs bear neutralizing activity, which is not sufficient to prevent the initiation of HIV-1 infection by blocking viral attachment to its CD4 receptor. 34 However, in HIV-1 infection, almost all individuals develop Abs capable of neutralizing autologous viruses in vitro. 46 Indeed, Abs with potent neutralizing activity against a broad range of HIV-1 strains across HIV-1 clades have been found in HIV-1-infected individuals.…”