The initial antibody response to HIV-1 can be detected as early as 1 week after infection and is directed to non-neutralizing epitopes in Env. The first antibodies are against gp41 region followed by the appearance of anti-gp120 antibodies a few weeks later and targeting the V3 loop [274, 290]. These binding antibodies mainly form immune complexes and don´t seem to have impact in viral replication suggesting that they are not responsible for the initial decline in plasma viral load [290]. However, although the first antibodies are not able to neutralize the virus, they may play a protective role in HIV-1 infection. For instance, a study in macaques has shown that Tat and Env binding antibodies confer some degree of protection against SHIV challenge despite the lack of neutralizing antibodies [291]. Moreover, the modest protection observed in RV144 (31.2%) trial may be in part due to binding antibodies that mediated antibody-dependent cell-mediated cytotoxicity (ADCC) and/or other non-neutralizing humoral effector functions [118, 131, 292]. Recently, a study performed in humanized mice using a replication-competent HIV-1 reporter virus expressing a heterologous HA-tag on the surface of infected cells and virions demonstrated that non-neutralizing antibodies can actually alter the course of HIV-1 infection, apply immune pressure on the infecting virus and also achieve modest levels of protection by a Fc receptor mediated mechanism. In this particular study, non-neutralizing antibodies were found to clear HIV-1 infected cells in vivo [293].
Neutralizing antibodies act by binding cell-free virus preventing the virion to infect the host cell [130]. However, it is still not clear (due to the variability in the experimental approaches) the relative activity of NAbs in cell-to-cell transmission, a major mechanism of HIV infection where HIV replicates more efficiently and rapidly through direct contact between cells[294, 295]. Overall, several studies have consistently demonstrated that NAbs are able to block HIV-1 infection at synapses, supporting the notion that cell-to-cell infection occurs through the direct transfer of virions accessible to the external environment. However, higher concentrations of specific NAbs (e.g. b12 and VRC01 against the CD4bs) are needed to inhibit cell-to-cell infection[296]. In addition, neutralizing polyclonal sera, which represent better the nature of the antibody response
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during natural infection, is less effective in inhibiting cell-to-cell infection compared with cell-free infection, although it varies significantly according to the sera[294, 297].
The first NAbs, targeting the variable regions of the HIV-1 envelope, arise several months post-infection and, although often potent, are directed to the infecting strain (i.e.
autologous virus) being unable to neutralize more divergent viruses (i.e. heterologous virus) [130, 132, 298-300]. Despite the high specificity of autologous NAbs, they exert a selective pressure on the virus that rapidly evolves to escape neutralization [130, 300].
Thus, it seems that NAbs appears sequentially and demonstrate temporal fluctuations consisting with the emerging of new escape variants [128, 300, 301]. An evidence that supports neutralization escape driven by autologous NAbs is the fact that contemporaneous viruses are less sensitive to autologous neutralization in comparison with earlier viruses[128]. Viral escape to avoid recognition is mediated by several features of Env that limit or block the access of antibodies to conserved neutralizing epitopes (Figure 12). Such features include carbohydrate shielding and shifting, conformation masking, steric occlusion, temporary epitope exposure (e.g. pre-fusion state form of gp41) and non-functional envelope spikes which are not expressed by mature functional spikes (e.g. gp120-gp41 monomers, gp41 stumps or uncleaved gp160 precursors) and may deviate the immune response from functional targets (reviewed in [298]). In fact, gp120 carries about 18 to 32 N-linked glycans which constitutes about 50% of the total molecular weight and function as a glycan armor avoiding antibody recognition[147, 302]. Also, the very limited number of gp160 glycoproteins per virion (between 21-42 SU molecules or 7-14 trimers per particle) likely reduce the ability of antibodies to bind simultaneously to two Env molecules (bivalent antibody binding) [303, 304]. Single amino acid substitutions, insertions and deletions in Env also contribute to viral escape [130, 300].
Despite of all these features some individuals are able to develop bNAbs targeting conserved functional sites on gp120 and gp41. In fact, during the course of infection, between 10-50% of HIV-1 infected individuals (depending on the definition of breadth and potency) develop broadly neutralizing antibody responses against diverse heterologous HIV-1 variants [305, 306]. Among them, few individuals (1%) called elite neutralizers develop highly potent and broad neutralizing responses.
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Figure 12- Envelope features defense mechanism against antibody recognition (adapted from [298]).
According to Simek et al, this elite activity is defined by the ability to neutralize, on average, more than one pseudovirus at an IC50 titer of 300 within a clade group and across at least four clade groups [307]. bNAbs generally arise only 2-4 years after seroconversion (in the chronic stage) and are absent in newly infected individuals suggesting that persistent infection and antigen exposure are required for their development [262, 308]. However, in rare cases bNAbs can arise 1 year following infection [309]. Development of bNAbs in HIV-1 infection is associated with the duration of infection, high viral load, low CD4+ counts and a higher frequency of T cell help (Tfh) in the periphery [254, 305]. Also, the early preservation of both Tfh and B cells is associated with the later development of breadth of neutralizing antibody responses in chronic HIV-1 infection [310]. All of these factors are consistent with the requirement of high levels of antigenic stimulation of B cells and the T cell help in the maturation of breadth through the infection. Nonetheless, individuals with low viral loads can also develop bNAbs suggesting that high viral load alone is not a determinant of breadth [311, 312]. In addition, viral genetic subtype may also be a contributing factor as exemplified by the more potent and broad humoral responses observed in subtype C chronically infected individuals compared with subtype B infected individuals [313, 314].
Interestingly, infants who acquired HIV-1 in utero, during delivery, or via breastfeeding can also mount bNAb responses as early as 20 months after infection suggesting that the development of bNAbs is not an inherent trait of adults and that even in early life there is an adequate B cell-functionality able to develop bNAbs against HIV-1. However, in this
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study, bNAbs epitopes were unclear with only a modest response observed in one infant against MPER in gp41[315].
Despite their protective role in vitro, bNAbs are unable to suppress viral replication in infected individuals due to viral escape [130, 300]. Demonstration that elicitation of bNAbs can be sufficient to prevent HIV-1 infection is now well documented based on passive immunization studies performed in animal models with human monoclonal antibodies (HuMAbs) with broadly neutralizing activity. In nonhuman primates protection was observed against viral challenge via intravenous, rectal and vaginal routes after passive immunization with broadly neutralizing monoclonal antibodies (e.g. F105, 2G12, 2F5, VRC01, PGT121, PGT126, b12, VRC07) [316-324]. Another study in macaques showed that the administration of PGT121 conferred sterilizing immunity against vaginal SHIV challenge at low concentrations [319]. Li and colleagues recently demonstrated that VRC01 was able to protect against HIV-1Ada vaginal and rectal challenge in hu-BLT mice (humanized mice) [318]. Also in humanized mice, passive administration of b12 and PGT126 provided sterilizing protection against repeated intravaginal HIV challenge [324].