CD4+ and production of antibodies (Smith et

CD4+ T cells are one of the critical components of immune system and it
direct and regulate the immune response to the pathogens, there by suppressing
unwanted immune response. The major immune protective functions are induction
of antigen-specific CD8+ memory T cell (Wiesel and Oxenius, 2012), B cell activation and production of
antibodies (Smith et al., 2000), macrophages to mediate microbicidal activity
at the site of infection (Charles A Janeway et al., 2001) and secretion of chemokines and cytokines to
regulate immune system (Kasakura, 1998).

CD4+ T cells play a versatile role in the pathogenesis of HIV infection
and it also serves as a primary cellular target for the establishment of HIV
Infection (Cummins and Badley, 2014).Virus-specific CD4+ T response has been
impaired during the primary HIV infection with subsequent loss of IL-2
secretion leads to progression of HIV infection (Younes et al., 2003). The magnitude and breadth of CD4+ T cell
response is associated the control of viremia during chronic HIV infection (Ranasinghe et al., 2012). Most of the HIV infected individuals develop
HIV specific CD4+ T cell response but its magnitude is low and smaller than the
CTL Response observed within the same individuals (Betts et al., 2001).However, CD4+ T cells in Elite controllers
shown to produce more IL-2 and found to be more polyfunctional than progressors
(Ferre et al., 2010).Activation of CD4+ T cells by vaccination increased
the risk of HIV acquisition among non-human primates (Bukh et al., 2014) and humans (Benlahrech et al., 2009) ,but recent RV144 vaccine trail demonstrate
that induction of antigen specific CD4+ T cells does not linked with increased
transmission risk among vaccinated individuals (Kim et al., 2015). Apart from helper T cell activity,
HIV-specific CD4+ T cells able to mediate direct cytolytic activity by
secreting granzyme A and helps in control of viral replication during acute
infection (Soghoian et al., 2012).

CD4+follicular T helper (TFH) cells, specialized CD4+ T cells that
provide signals to B cells for the formation of germinal centers (GCs) to
produce antibodies (Vinuesa et al., 2016). TFH cells are major source of viral reservoir
in the lymph node (Perreau et al., 2013)and blood (Pallikkuth et al., 2016)and it is expanded during the chronic HIV
infection (Lindqvist et al., 2012). Due to continued antigenic stimulation, TFH
cells lost their functional capacity to help B cells leads to hypergammaglobulinemia
that is characteristic of B cell dysfunction(Ruffin et al., 2017). TFH cells secrete IL-21 which stimulates B
cell, but it also enhances antiviral activity of CD8 T cells (Xin et al., 2015). Interestingly, neutralizing antibody breadth
has been associated with the frequencies of  peripheral TFH cells (Locci et al., 2013) and has become an important area in HIV
vaccine field especially with induction of neutralizing antibodies (Chevalier
and Weiss, 2013). 








Broadly neutralizing
antibodies (bnAbs) are attractive targets for vaccine development, because of
their ability to neutralize diverse variants of HIV- 1 and remains an unachieved
goal of prophylactic HIV- 1 vaccine strategies. In the last 20 years, numerous
studies investigated the antibody response to HIV and generated key information
on epitope specificity, neutralization its breadth, potency and in-vivo
neutralization activity. Further, recent isolation of broadly neutralizing
antibodies and its in-vivo passive experiments highlighted its potential valuable
tools for HIV prevention and treatment. Importantly, both the neutralizing and
non-neutralizing antibodies could likely contribute for its in-vivo efficacy. Virus
neutralization is the well-characterized antibody function during HIV-1
et al., 2000), however antibodies could potentially activate several effector
functions as depicted in the Figure. 10
that includes;complement-mediated
lysis of free virus and infected cells (Sullivan
et al., 1996),Fc mediated opsonization
and phagocytosis of virus particles (Sips
et al., 2016), antibody-dependent
cellular cytotoxicity (ADCC) against infected cells(Lee
and Kent, 2017).


Initial and autologous antibody response to HIV infection

The first B cell
response occurs after 8 days after the appearance of detectable viremia (Fiebig Stage II,Fig.11)  in form of immune complexes and after 13 days
free IgM antibodies (Fiebig Stage
III,Fig.11) appears against gp41 region(Tomaras
et al., 2008). Later time point IgG and IgA antibodies continue to appear in the
plasma with specificities against p24 and p55 at day 18, p17 at day 31 and p31
at day 53 respectively(Tomaras
and Haynes, 2009) . The gp120 antibodies was found to be appeared after 4 weeks after the
viremia and it directed against V3 loop (Davis
et al., 2009a). These acute gp41- and gp120-specific antibodies are non-neutralizing
in nature and ineffective in control of viremia during acute infection and do
not exert any selective pressure on the envelope (Tomaras
et al., 2008). These gp41antibodies are polyreactive
and highly mutated in nature and it was elicited due to priming of B cells by non-HIV
antigen in the intestinal microbiota prior to HIV infection (Trama
et al., 2014).
The initial neutralization response appears
approximately after 12 weeks (Fiebig
Stage V,Figure.11) from the date of infection(Deeks
et al., 2006).

In general, this
initial antibody response is narrow and effective only against early autologous
viruses (Li et al., 2006;
Richman et al., 2003)and T-cell adapted
strains (Beddows et al.,
1998). Consequently, the
viruses can easily escape from these antibodies with the emergency of escape
mutants in the plasma sample, which directly indicates that these antibodies
exert immune pressure on the virus(Wei et al., 2003a).The pressure exerted by the antibodies comes
with a fitness cost up to 24% on the escape variants (Bar et al., 2012) and demonstrated a
seven-fold drop in viremia in a study participant with autologous anti-C3
antibodies. In contrast, few studies failed to demonstrate this effect(van Gils et al.,
2010). Moreover, these
neutralizing antibodies take longer duration to reach biologically significant
levels in the plasma after the exposure of transmitted founder virus to the
immune system (Davis et al., 2009a;
Rong et al., 2009).The escape mutation
occurs through substitutions, insertions and deletions in the glycan shield there
by shifting the glycan positions to evade neutralizing antibodies (Bunnik et al., 2010;
Richman et al., 2003).