A good example of the role that antibodies can play against viruses is hepatitis B where the recombinant hepatitis B surface antigen vaccine induces neutralizing antibodies which are protective against infection. Indeed, shortly after primary infection in human, HIV-1 stimulates a humoral immune response which results in the production of antibodies directed against most of the viral structural components. .A particular subset of antibodies is directed against HIV-envelope gp120 and gp41, which are the surface (SU) and transmembrane (TM) glycoproteins. It has also been shown that mothers who transmit HIV to their children have fewer neutralizing anti-HIV antibodies when compared to mothers who do not transmit HIV.

Antibodies against Molecules used by HIV for Infection

–Against CD4: Caskey (Nature, 2015, “Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117) reports the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody.

Anti-CD4 receptor antibodies: Another approach is the use of anti-CD4 receptor antibodies as gp 120 surrogates to boost or elicit an in vivo immune response (“active immunotherapy”) that includes high titers of HIV neutralizing antibodies. McDougal, J.S., et al., J. Immunology, 137:2937(1986) and Chanh, T.C., et al., PNAS USA 84:3891 (1987).

–Against CCR5: PRO140 (CytoDyn Inc.) is an example of an antibody directed against CCR, the molecule which HIV uses to enter cells. PRO140 appears to block entry of HIV through CCR5 without affecting the normal functions of CCR5. 

Antibodies against HIV itself

–Against gp41: US Patent No. 5,459,060, US Patent 5,777,074,US Patent No. 6,008,044,US Patent No. 6,083,504 all assigned to Bioclonetics Incorporated, describes a human monoclonal antibody which binds to a conserved peptide of of gp41 and, as a consequence biologically blocks syncytia formation between HIV-1 virally infected human lymphocytes and uninfected lymphocytes (CD4+ Cells). 

–Against gp120: PCT/US02/33165 filed 16 Oct 2002 discloses a novel anti-HIV human monoclonal antibody called X5. The X5 antibody binds to a unique epitope on gp120 that is induced by interaction between gp120 and the receptor CD4 and enhaced by the coreceptor CCR. It shows strong activity at very low levels. see also laboratory of Dimiter Dimitrov .

However there are a number of problems with this approach due to  the high variability in surface proteins of HIV. This is also why the immune system is not able to control the virus by itself. Research is focusing on invariant regions of the surface proteins of the virus and using these regions as a vaccine.  However, the  ability of the selected immunogen to elicit sufficiently high titers of HIV neutralizing antibodies and the ability of those anti-HIV antibodies to neutralize a broad group of HIV types or isolates still remains a problem

Antibodies directed against conserved epitopes of HIV will likely decrease the mergence of neutralization resistant mutants. Several neutralization epitopes have been identified on the external membrane glycoprotein gp120. These include (a) a region near the amino terminus which has been shown to be important for virus entry; (b) the V3 hypervariable loop; (c) the CD4 binding domain and (d) a region which spans the carboxy terminus of gp120 and the amino terminus of gp41. For example, the “crown” sequence in the V3 loop of gp120 is conserved to a considerable degree. About 30% of North American HIV isolates have the crown sequence designated MN.

T cell engagers:

CD4-anti-CD3 T cell engagers:

Wabl (WO 93/08829) discloses a method for directing a cytotoxic T cell to an HIV-1-infected clls by contacting the infected cell with a bispecific molecules that includes two binding domains, the first binding comain includes a CD4 domain and the second binding domain includes an anti-CD3 binding region. Thus one specific binding region of the molecule consists of a protion or all of CD4 variable region that is capable of binding to HIV gp120 while the other binding region exhibits specific binding affinity for a cytotoxic T cell, typically via an anti-CD3 binding region of an antibody. HIV cannot mutate out of the binding capability of CD4 without losing its ability to infect cells via theri membrane CD4 molecule. This is an advantage over using an anti-gp120 monoclonal antibody. CD4 sequences containing any of the CD4 domains invovled in binding to gp120 are fused to the anti-CD3 binding sequence. 

Problems association with Antibody Design against HIV and Strategies to overcome these problems: 

Neutralizing antibodies are elicited by most, if not all, successful vaccines. However, immunogens that are able to elicit neutralizing antibodies to a broad range of primary HIV-1 isolates have not been found. However, a few rare, broadly neutralzing monoclonal antibodies that have been isolated from patients protect against viral challenge in animal models. Their epitopes include regions on gp41, the CD4-binding site of gp120 and part of the carbohydrate masked silent face of gp120. A molecular understanding of the binding of these broadly neutralizing antibodies to their cognate envelope epitopes should facilitate rational HIV-1 vaccine design.

One such broadly neutralizing human antibody 2G12 binds with nanomolar affinity to gp120. This antibody recognizes terminal Manalpha1-2Man-linked moieties, contributed by oligomannose-type sugars that form a cluster on the silent face of gp120. This face is designated “silent” because the oligosaccharides shield potential antigenic epitopes and also because oligosaccharides attached to the viral coate proteins are processed by the host and are, therefore, unlikely to be immunogenic and also because glycosylated proteins are synthesized as a collection of glycoforms in which multiple sugars can be present at a single site, which dilutes any potential antigenic response. Furthemore, carboydrate protein interactions are usually much weaker than protein-protein interactions and restrict antibodies from approaching their expected range of nanomolar binding affinities. Nevertheless, antibody 2G12 binds with high affinity to carbohydrate epitopes on gp120. The proposed mode of binding of 2G12 is reminiscent of one of the suggested mechanisms of multivalent recognition by animal lectins. A C-type lectin, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin) also binds carbohydrates on the envelope of HIV and facilitates viral infection of CD4+ T cells. 

A human monoclonal Fab fragment (Fab b12) derived from a combinatorial antibody library prepared from bone marrow of a long-term, asymptomatic HIV-1-seropositive donor has also been shown to be potent in the neutralization of HIV-1.

Affinity Maturation Techniques

One of the most interesting prospects for future antibody develop to neutralize HIV is the concept that any successful neutralizing antibody will be an antibody which has a high degree of affinity maturation. In this respect, research from the Vaccine Research Center (VRC) at the Nationla Institute of Allergy and Infectious Diseases (NIAID) reported the isolation of 3 broadly neutralizing antibodys (bNAbs) against HIV as well as the structure of the antigen binding portion of one such antibody called VRC01 which bound to the HIV gp120 core protein. VRC01 was shown to neutralize 91% of the HIV strains tested. Interestingly, VRC01 was shown to have an unusually high degree of affinity maturation. About 30% or more than 60 amino acids of the variable region differed from the germline sequence. Other studies showed that affinity maturation is very important for the success of other HIV neutralizing antibodies. For example, researches at IAVI and The Scripps Research Institute showed about 20% affinity maturation. Interestingly, versions of these antibodies that were almost completely reverted to germline showed no or poor neutralization. This suggests that current strategies to develop vaccines that are based on HIV Env as an immunogen may be fruitless because if Env does not bind to the germline precursors of neutralizing antibodies, it will not induce the affinity maturation process that is necessary to make the antibodies. To address these problems, research are now looking for immunogens that can bind to the germline precursors so to get the process of affinity maturation moving. In other words, the vaccine should contain immunogens which are different from HIV proteins which can bind the germline precursors. Once affinity maturation is initiated, Env could be used.

Catalytic Antibodies: 

It has been demonstrated that IgAs from the saliva and serum of humans without HIV infection have the ability to catalyze the cleavage of gp120 efficiently compared to IgGs. The activity of serum IgAs was increased in seropositive subjects with slow progression to AIDS but not rapid progressors. The selective expression of catalytic activity by IgAs appears to be mediated by recognition of the gp120 SAg site and suggests catalytic immunity as a host resistance factor in HIV infection. The possibility of a protective role for Abs that bind the gp120 SAg site is suggested by (a) binding of the gp120 SAg site by serum IgG from HIV seronegative individuals at risk for HIV infection is negatively correlated with the incidence of subsequent HIV infection and (b) intravenous infusion of pooled IgG from uninfected monkeys protecs recipient monkeys form subsequent challenge with simian immunodeficiency virus, a frequently used model fo HIV-1 infection. (Paul, US 11988761).

Antibodies against Cytokines

 IL-1: Briesen (Res. Virol. 1991, 142 (197-204) disclose that interleukein-1 9IL1) accelerated and increased HIV replication in blood-borne monocytes 9MO) differentating into mature macrophages 9MAC). In particular, IL1alpha and especially IL1beta augmented HIV replication.

 IFNs:  Briesen (Res. Virol. 1991, 142 (197-204) disclose that IFN alpha, IFNbeta or IFNgamma inhibited HIV replication in blood-borne monocytes 9MO) differentating into mature macrophages 9MAC). In particular, IL1alpha and especially IL1beta augmented HIV replication.