Initial B-Cell Responses to Transmitted Human Immunodeficiency Virus Type 1: Virion-Binding Immunoglobulin M (IgM) and IgG Antibodies Followed by Plasma Anti-gp41 Antibodies with Ineffective Control of Initial Viremia

Abstract

A window of opportunity for immune responses to extinguish human immunodeficiency virus type 1 (HIV-1

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…The earliest changes to the virus population are driven by the CD8 + T‐cell response that is induced as viremia increases39 and places strong selection pressure on the virus, resulting in complete turnover of the virus pool within the first few weeks of infection 40. The development of antibody responses follows a pattern, with antiviral antibodies being detected first as immune complexes41 followed by free antibody directed at the HIV‐1 envelope (Env) glycoprotein 41 (gp41) subunit,41, 42 and then by the development of Env glycoprotein 120 (gp120)‐binding antibodies 41. These early antibody responses do not neutralize or place selective pressure on virus evolution41; antibodies capable of neutralizing autologous viruses are not detectable until weeks to months after infection is established19, 20 and have little to no activity against heterologous HIV‐1 strains 43.…”

“…The development of antibody responses follows a pattern, with antiviral antibodies being detected first as immune complexes41 followed by free antibody directed at the HIV‐1 envelope (Env) glycoprotein 41 (gp41) subunit,41, 42 and then by the development of Env glycoprotein 120 (gp120)‐binding antibodies 41. These early antibody responses do not neutralize or place selective pressure on virus evolution41; antibodies capable of neutralizing autologous viruses are not detectable until weeks to months after infection is established19, 20 and have little to no activity against heterologous HIV‐1 strains 43. The initial gp41‐directed antibody response is polyreactive and the antibodies are highly mutated,42 and evidence indicates that at least some early responding B cells are primed prior to infection by non‐HIV‐1 antigens such as proteins contained in intestinal microbiota 44…”

“…Acutely HIV‐1‐infected individuals do not make bnAbs,41, 43 but during chronic HIV‐1 infection, neutralization breadth develops to a greater or lesser degree in each person 45, 46, 47. Breadth of plasma neutralizing activity develops incrementally,48 and evidence suggests that protracted exposure to HIV‐1 Env is required 22, 23, 24, 47, 48, 49, 50.…”

“…It is possible that trafficking of the negative regulatory factor (Nef) protein from HIV‐1‐infected macrophages to B cells may alter class switching and germinal center (GC) responses,58 but dysfunction is also likely driven by the early cytokine storm59 and ongoing immune dysfunction caused by HIV‐1 infection of T cells. B‐cell dysregulation is evidenced by the delayed antibody response in acute HIV‐1 infection,41 an increase in the proportion of activated memory B cells and exhausted B cells, non‐specific plasmablast activation (leading to polyclonal immunoglobulin production), and a decline in the frequency of long‐lived plasma cells 42, 60, 61, 62, 63. In addition, Env‐specific B cells are found in the activated and exhausted B‐cell subsets in viremic individuals 64.…”

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…In individuals, HIV-1 infection is usually initiated by one or a few transmitted/founder (TF) viruses (2), and within each infected person, evolves to extraordinary diversity shaped by antibody and T cell responses (3, 4). Moreover, virus integration occurs early on in infection, before a protective antibody or T cell response can occur (5). Therefore, elicitation of protective antibodies before HIV-1 transmission will be required to achieve protection (6, 7).…”