RV144 is the only clinical vaccine trial to date which provided a marginal but statistically significant reduced rate of infection  as well as an independent correlate of risk (COR) of HIV infection: an inverse relationship between the incidence of infection and the level of Abs binding to a V1V2CaseA2-gp70 fusion protein [32–34]. The V1V2CaseA2-gp70 fusion protein preferentially reacts with V2i mAbs, and indeed, several V2i mAbs have been selected from the cells of HIV-infected individuals using this reagent, and these V2i mAbs are highly cross-clade reactive [35,36]. In this context, it is noteworthy that while V1V2CaseA2-gp70 carries the V1V2 sequence from a clade B strain , infections occurring in the RV144 participants were primarily because of clade AE (CRF01_AE), the predominant circulating strain in Thailand, and this supports the hypothesis that the V2 Abs implicated in the inverse COR were cross-clade reactive.
Notably, in human vaccine studies other than RV144, the induction of highly reactive and functional V2-specific Abs has not been strong, for example in studies such as VAX003, VAX004 and HVTN100 [5,38,39]. It is hypothesized that the gp120 of the clade AE A244 strain used in RV144 is unusual in its ability to efficiently induce V2 Abs. Thus, for example, the immunogens used in HVTN100 [ALVAC-HIV (vCP2438) and bivalent Subtype C gp120 s (1086 and TV1)], which was the precursor of the ongoing phase III HVTN702 study in South Africa, induced a markedly poorer V2 response than that attained in RV144 . These findings are of particular interest in the context of recent studies in which robust V2i and V2p Ab responses have been elicited using V2-targeting vaccine constructs in rabbits [40,41] and NHPs . Notably, in the latter study, the use of a trimeric V1V2A244-scaffold fusion protein as part of an immunogen cocktail appeared to be particularly effective in inducing broadly reactive and functional V2 Abs.
In addition to the inverse COR with V2i Abs, a similar role for V2p Abs has been documented. Thus, studies with plasma from RV144 vaccinees demonstrated an inverse COR in terms of the Ab response to linear V2 peptides tested by microarray , and the correlations of Abs cross-reactive with V2 peptides representing different HIV clades were at least as significant as the correlation seen with the primary variable generated using the V1V2CaseA2-gp70 fusion protein. As noted, linear and cyclic V2 (cV2) peptides preferentially assume a structure when complexed with specific V2p mAbs in which the C-strand is in an α-helical configuration [19,29▪,30▪], and two such V2p mAbs were isolated from circulating cells of an individual receiving the RV144 vaccine regimen . Thus, we know from polyclonal and mAb studies emanating from RV144 that V2p Abs recognizing the α-helix in the C-strand of V2 were induced by the RV144 vaccine and that they constitute an inverse COR ( and Table 1) [32,43–48,49▪,50,51,52▪]. Additional V2p mAbs have recently been isolated from individuals infected with clade C [29▪,30▪]. All of these V2p mAbs have been crystallized and reveal the targeted epitope in the V2 C-strand as an α-helix or helix-loop, and, like the plasma V2p polyclonal Abs in RV144 vaccinees , these mAbs are cross-clade reactive (Fig. 2A) .
The original observation of an inverse COR in RV144 has been supported by many subsidiary studies of the RV144 data [3,4,43,53,54]. Nonetheless, there are critics who remain skeptical of the RV144 correlates analyses . This skepticism is now tempered by both active and passive immunization studies from many laboratories showing correlates of protection from SIV and SHIV infection with the presence of V2 Abs (Table 1).
In an NHP vaccine study using vaccine regimens consisting of Ad26 and/or modified vaccinia Ankara vector-based vaccines expressing SIVSME543 gag, pol and Env antigens with subsequent intrarectal (i.r.) challenges with SIVmac251, there was at least 80% reduction in per-exposure probability of infection . The strength of Ab binding to a biotinylated cyclic V2 peptide from SIVSME543 correlated positively with the number of challenges required to establish infection (P < 0.0001).
Most recently, an RV144-like vaccine regimen was tested in NHPs that were challenged with SHIVBaL. All three unimmunized animals were infected after two i.r. challenges, but in five of the nine immunized macaques, tight control of viremia was noted as reflected by only transient and low plasma viral load (PVL) measurements, with no measurable virus in tissues at necropsy 13 weeks after challenge. Luminex studies of the plasma from these animals showed a correlate of protection from SHIVBaL with Abs of the V2p type that were reactive with V1V21086-tags , a reagent in which the V2 C-strand preferentially adopts an α-helical conformation as shown by circular dichroism [52▪].
Neutralizing Abs were not an inverse COR in the RV144 vaccine trial, suggesting that non-neutralizing Ab effects were critical. These effects could be mediated by either the Fab portion of the Ab which binds to antigens on the surface of the virus or virus-infected cell and/or by the Fc portion of the Ab which binds to Fc receptors (FcRs) after the Fab fragment binds to its antigen.
Neutralization of virus infectivity is the most frequently measured antiviral activity, resulting as a function of the attachment of Abs to virions. However, several other phenomena belong to this category of antiviral functions and appear to play a critical role in vivo. These include:
Many Abs Mediate antiviral effects because of their ability to bind to infected cells and/or virions, leading to conformational changes in the Fc fragment which allow it to bind to FcRs on the surface of various cell types such as T cells, monocyte/macrophages, polymorphonuclear granulocytes, dendritic cells, and so on. These Abs include both bnAbs and Abs that are poor or non-neutralizers, can be specific for various regions of the gp120 and gp41 Env proteins (Fig. 3 and [19,30▪,40,54,64–70]), and can bind to the Env trimer in its different states (closed, partially open or fully open [16▪]). The Fc/FcR interaction initiates antiviral activities that include Ab-dependent cellular phagocytosis (ADCP) and Ab-dependent cellular cytotoxicity [2,4,54,71–73] as well as complement-mediated virolysis [39,74–76]. Many of these mechanisms have been associated with reduced risk of infection. For example, ADCP has been associated with reduced HIV infection risk in humans [39,77] and with SIV infection in NHPs , and Ab-dependent complement activation and deposition [78,79▪] as well as Ab-dependent cell-mediated viral inhibition have been shown to contribute to control of SIV and SHIV [80–83].
The first and only independent correlate of reduced risk of HIV infection in humans was identified by studies of participants in the RV144 clinical vaccine trial: a robust Ab response to the V1V2 region of the virus gp120 Env glycoprotein. Subsequent to this observation, several active and passive immunization studies in NHPs identified the presence and level of V2 Abs as correlates of protection from SIV and SHIV infections. Currently, 11 vaccine studies in humans and NHPs (summarized in Table 1) support the role of V1V2-specific Abs in protection. In each case, the Abs involved displayed little or no neutralizing activity but mediated other antiviral activities. Protection was documented against viruses heterologous to the strains used in the vaccines. These studies suggest a new paradigm for vaccine development: protection from and/or control of infection can be achieved with Abs that are induced by existing vaccine constructs, are effective against heterologous viruses, do not display broad and potent neutralizing activity and mediate a variety of non-neutralizing Fab-mediated and Fc-mediated antiviral activities.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Liu P, Overman RG, Yates NL, et al. Dynamic antibody specificities and virion concentrations in circulating immune complexes in acute to chronic HIV-1 infection. J Virol 2011; 85:11196–11207.
2. Chung AW, Kumar MP, Arnold KB, et al. Dissecting polyclonal vaccine-induced humoral immunity against HIV using systems serology. Cell 2015; 163:988–998.
3. Yates NL, Liao HX, Fong Y, et al. Vaccine-induced Env V1-V2
IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination. Sci Transl Med 2014; 6:228ra39.
4. Chung AW, Ghebremichael M, Robinson H, et al. Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines
. Sci Transl Med 2014; 6:228ra38.
5. Balasubramanian P, Williams C, Shapiro MB, et al. Functional antibody response against V1V2 and V3 of HIV gp120 in the VAX003 and VAX004 vaccine trials. Sci Rep 2018; 8:542.
6▪. Yates NL, deCamp AC, Korber BT, et al. HIV-1 envelope glycoproteins from diverse clades differentiate antibody responses and durability among vaccinees. J Virol 2018; 92: e01843-17.
Analysis of vaccine-elicited V1V2 binding antibody in longitudinal samples from the RV144 clinical trial revealed a striking heterogeneity among individual vaccinees in maintaining durable responses. These data support the idea that a major goal for vaccine development is to improve antibody levels, breadth and durability at the population level.
7▪. Ackerman ME, Das J, Pittala S, et al. Route of immunization defines multiple mechanisms of vaccine-mediated protection against SIV. Nat Med 2018; 24:1590–1598.
The route of immunization plays a critical role for phagocytic Fc-effector Ab activity in protection from SIV, driving Fc activity via distinct innate effector cells and antibody isotypes. The same correlates predict protection from SHIV infection. Thus, functional humoral mechanisms initiated by distinct vaccination routes and immunization strategies are pivotal for inducing multiple, potentially complementary correlates of immunity.
8. Miller-Novak LK, Das J, Musich TA, et al. Analysis of complement-mediated lysis of simian immunodeficiency virus (SIV) and SIV-infected cells reveals sex differences in vaccine-induced immune responses in rhesus macaques. J Virol 2018; 92:
9. Bradley T, Pollara J, Santra S, et al. Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge. Nat Commun 2017; 8:15711.
10. Srivastava IK, Stamatatos L, Kan E, et al. Purification, characterization, and immunogenicity of a soluble trimeric envelope protein containing a partial deletion of the V2
loop derived from SF162, an R5-tropic human immunodeficiency virus type 1 isolate. J Virol 2003; 77:11244–11259.
11. Barnett SW, Srivastava IK, Kan E, et al. Protection of macaques against vaginal SHIV challenge by systemic or mucosal and systemic vaccinations with HIV-envelope. AIDS 2008; 22:339–348.
12. Barouch DH, Stephenson KE, Borducchi EN, et al. Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell 2013; 155:531–539.
13. Kwon YD, Finzi A, Wu X, et al. Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc Natl Acad Sci U S A 2012; 109:5663–5668.
14. Mao Y, Wang L, Gu C, et al. Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer. Nat Struct Mol Biol 2012; 19:893–899.
15. Munro JB, Gorman J, Ma X, et al. Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions. Science 2014; 346:759–763.
16▪. Wang H, Barnes CO, Yang Z, et al. Partially open HIV-1 envelope structures exhibit conformational changes relevant for coreceptor binding and fusion. Cell Host Microbe 2018; 24:579–592.e4.
Cryo-electron micrographic structures of SOSIP with various Abs and/or CD4 reveal the structure of the displaced V1V2 and reveal its structures.
17. McLellan JS, Pancera M, Carrico C, et al. Structure of HIV-1 gp120 V1/V2
domain with broadly neutralizing antibody PG9. Nature 2011; 480:336–343.
18. Pan R, Gorny MK, Zolla-Pazner S, Kong XP. The V1V2 region of HIV-1 gp120 forms a five-stranded beta barrel. J Virol 2015; 89:8003–8010.
19. Liao H-X, Bonsignori M, Alam SM, et al. Vaccine induction of antibodies
against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2. Immunity 2013; 38:1–11.
20. Powell RLR, Totrov M, Itri V, et al. Plasticity and epitope
exposure of the HIV-1 envelope trimer. J Virol 2017; 91: e00410-17.
21. Gorny MK, Stamatatos L, Volsky B, et al. Identification of a new quaternary neutralizing epitope
on human immunodeficiency virus type 1 virus particles. J Virol 2005; 79:5232–5237.
22. Kimura T, Wang XH, Williams C, et al. Human monoclonal antibody 2909 binds to pseudovirions expressing trimers but not monomeric HIV-1 envelope proteins. Hum Antibodies
2009; 18 (1–2):35–40.
23. Pancera M, Zhou T, Druz A, et al. Structure and immune recognition of trimeric prefusion HIV-1 Env. Nature 2014; 514:455–461.
24. Walker LM, Phogat SK, Chan-Hui PY, et al. Broad and potent neutralizing antibodies
from an African donor reveal a new HIV-1 vaccine target. Science 2009; 326:285–289.
25. Lee JH, Andrabi R, Su CY, et al. A broadly neutralizing antibody targets the dynamic HIV envelope trimer apex via a long, rigidified, and anionic beta-hairpin structure. Immunity 2017; 46:690–702.
26. Mayr LM, Cohen S, Spurrier B, et al. Epitope
mapping of conformational V2
-specific anti-HIV human monoclonal antibodies
reveals an immunodominant site in V2
. PLoS One 2013; 8:e70859.
27. Gorny MK, Moore JP, Conley AJ, et al. Human anti-V2
monoclonal antibody that neutralizes primary but not laboratory isolates of HIV-1. J Virol 1994; 68:8312–8320.
28. Nyambi PN, Mbah HA, Burda S, et al. Conserved and exposed epitopes on intact, native, primary human immunodeficiency virus type 1 virions of group M. J Virol 2000; 74:7096–7107.
29▪. Wibmer CK, Richardson SI, Yolitz J, et al. Common helical V1V2 conformations of HIV-1 Envelope expose the alpha4beta7 binding site on intact virions. Nat Commun 2018; 9:4489.
Structural studies of the epitope recognized by new V2p mAbs derived from patients infected with HIV.
30▪. van Eeden C, Wibmer CK, Scheepers C, et al. V2
-directed vaccine-like antibodies
from HIV-1 infection identify an additional K169-binding light chain motif with broad ADCC activity. Cell Rep 2018; 25:3123–3135.e6.
Functional studies of new V2p mAbs derived from HIV-infected individuals.
31. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009; 361:2209–2220.
32. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune correlates analysis of the ALVAC-AIDSVAX HIV-1 vaccine efficacy trial. N Engl J Med 2012; 366:1275–1286.
33. Zolla-Pazner S, deCamp AC, Cardozo T, et al. Analysis of V2
antibody responses induced in vaccinees in the ALVAC/AIDSVAX HIV-1 vaccine efficacy trial. PLos One 2013; 8:e53629.
34. Zolla-Pazner S, DeCamp AC, Gilbert PB, et al. Vaccine-induced IgG antibodies
to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection. PLos One 2014; 9:e87572.
35. Gorny MK, Pan R, Williams C, et al. Functional and immunochemical cross-reactivity of V2
-specific monoclonal antibodies
from human immunodeficiency virus type 1-infected individuals. Virology 2012; 427:198–207.
36. Pinter A, Honnen WJ, He Y, et al. The V1/V2
domain of gp120 is a global regulator of sensitivity of primary human immunodeficiency virus type 1 isolates to neutralization by antibodies
commonly induced upon infection. J Virol 2004; 78:5205–5215.
37. Pinter A, Honnen WJ, Kayman SC, et al. Potent neutralization of primary HIV-1 isolates by antibodies
directed against epitopes present in the V1/V2
domain of HIV-1 gp120. Vaccine 1998; 16:1803–1811.
38. Shen X, Moodie Z, McMillan A, et al. V1V2 IgG and Antibody Fc Effector Functions in a Subtype C ALVAC-HIV and Bivalent Subtype C gp120/MF59 HIV-1 Vaccine Trial in South Africa. HIV Research for Prevention. Madrid. 2018. Abstract OA02.03.
39. Perez LG, Martinez DR, deCamp AC, et al. V1V2-specific complement activating serum IgG as a correlate of reduced HIV-1 infection risk in RV144. PLoS One 2017; 12:e0180720.
40. Zolla-Pazner S, Powell R, Yahyaei S, et al. Rationally-designed vaccines
targeting the V2
region of HIV-1 gp120 induce a focused, cross clade-reactive biologically functional antibody response. J Virol 2016; 90:10993–11006.
41. Jiang X, Totrov M, Li W, et al. Rationally designed immunogens targeting HIV-1 gp120 V1V2 induce distinct conformation-specific antibody responses in rabbits. J Virol 2016; 90:11007–11019.
42. Hessell AJ, Powell R, Jaing X, et al. Multimeric epitope
-scafold HIV vaccines
target V1V2 and differentially tune polyfunctional antibody responses. Cell Rep 2019; in press.
43. Gottardo R, Bailer RT, Korber BT, et al. Plasma IgG to linear epitopes in the V2
and V3 regions of HIV-1 gp120 as correlates of infection risk in the RV144 vaccine efficacy trial. PLoS One 2013; 8:e75665.
44. Barouch DH, Liu J, Li H, et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature 2012; 482:89–93.
45. Pegu P, Vaccari M, Gordon S, et al. Antibodies
with high avidity to the gp120 envelope protein in protection from simian immunodeficiency virus SIV(mac251) acquisition in an immunization regimen that mimics the RV-144 Thai trial. J Virol 2013; 87:1708–1719.
46. Gordon SN, Doster MN, Kines RC, et al. Antibody to the gp120 V1/V2
loops and CD4+ and CD8+ T cell responses in protection from SIVmac251 vaginal acquisition and persistent viremia. J Immunol 2014; 193:6172–6183.
47. Roederer M, Keele BF, Schmidt SD, et al. Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV. Nature 2014; 505:502–508.
48. Vaccari M, Gordon SN, Fourati S, et al. Adjuvant-dependent innate and adaptive immune signatures of risk of SIV acquisition. Nat Med 2016; 22:762–770.
49▪. Hessell AJ, Shapiro MB, Powell R, et al. Reduced cell-associated DNA and improved viral control in macaques following passive transfer of a single anti-V2
monoclonal antibody and repeated SHIV challenges. J Virol 2018; 92: e02198-17.
Efficacy of V2i mAbs passively administered to NHPs and challenged with SHIVBaL.
50. Singh S, Ramirez-Salazar EG, Doueiri R, et al. Control of heterologous simian immunodeficiency virus SIVsmE660 infection by DNA and protein coimmunization regimens combined with different toll-like-receptor-4-based adjuvants in macaques. J Virol 2018; 92: e00281-18.
51. Hessell AJ DM, Philip B, Shilpi P, et al. Tight Control of SHIV BaL.P4 Challenge in Rhesus Macaques Co-immunized With DNA and Protein HIV Vaccine Regimen. HIV Research for Prevention; Madrid. 2018. Abstract OA09.4.
52▪. Weiss S, Vincenza I, Ruimin P, et al. Tight Control of SHIVBaL in Rhesus Macaques Immunized With gp160 DNA + gp120 Proteins (Clades E and B) Correlates With V2p Antibodies
. HIV Research for Prevention; Madrid. 2018. Abstract OA14.06LB.
First description of a correlate of protection from SHIV infection with the presence of V2p Abs.
53. Rolland M, Edlefsen PT, Larsen BB, et al. Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2
. Nature 2012; 490:417–420.
54. Pollara J, Bonsignori M, Moody MA, et al. HIV-1 vaccine-induced C1 and V2
synergize for increased antiviral activities. J Virol 2014; 88:7715–7726.
55. Desrosiers RC. Protection against HIV acquisition in the RV144 trial. J Virol 2017; 91: e00905-17.
56. Mayr LM, Su B, Moog C. Non-neutralizing antibodies
directed against HIV and their functions. Front Immunol 2017; 8:1590.
57. Gach JS, Bouzin M, Wong MP, et al. Human immunodeficiency virus type-1 (HIV-1) evades antibody-dependent phagocytosis. PLoS Pathog 2017; 13:e1006793.
58. Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996; 271:1582–1586.
59. Alexander MR, Sanders RW, Moore JP, Klasse PJ. Short Communication: virion aggregation by neutralizing and nonneutralizing antibodies
to the HIV-1 envelope glycoprotein. AIDS Res Hum Retroviruses 2015; 31:1160–1165.
60. Liu P, Yates NL, Shen X, et al. Infectious virion capture by HIV-1 gp120-specific IgG from RV144 vaccinees. J Virol 2013; 87:7828–7836.
61. Arthos J, Cicala C, Martinelli E, et al. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 2008; 9:301–309.
62▪. Lertjuthaporn S, Cicala C, Van Ryk D, et al. Select gp120 V2
domain specific antibodies
derived from HIV and SIV infection and vaccination inhibit gp120 binding to alpha4beta7. PLoS Pathog 2018; 14:e1007278.
HIV and SIV V2 mAbs elicited by both vaccination and infection block the interaction of V2 and α4β7.
63. Peachman Kristina K, Karasavvas N, Chenine A-L, et al. Identification of new regions in HIV-1 gp120 variable 2 and 3 loops that bind to α4β7 integrin receptor. PLoS One 2015; 10:e0143895.
64. Alvarez RA, Hamlin RE, Monroe A, et al. HIV-1 Vpu antagonism of tetherin inhibits antibody-dependent cellular cytotoxic responses by natural killer cells. J Virol 2014; 88:6031–6046.
65. Holl V, Peressin M, Decoville T, et al. Nonneutralizing antibodies
are able to inhibit human immunodeficiency virus type 1 replication in macrophages and immature dendritic cells. J Virol 2006; 80:6177–6181.
66. Musich T, Li L, Liu L, et al. Monoclonal antibodies
specific for the V2
, V3, CD4-binding site, and gp41 of HIV-1 mediate phagocytosis in a dose-dependent manner. J Virol 2017; 91: e02325-16.
67. Mayr LM, Decoville T, Schmidt S, et al. Nonneutralizing antibodies
targeting the V1V2 domain of HIV exhibit strong antibody-dependent cell-mediated cytotoxic activity. Sci Rep 2017; 7:12655.
68. Chung AW, Crispin M, Pritchard L, et al. Identification of antibody glycosylation structures that predict monoclonal antibody Fc-effector function. AIDS 2014; 28:2523–2530.
69. Burton DR, Hessell AJ, Keele BF, et al. Limited or no protection by weakly or nonneutralizing antibodies
against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody. Proc Natl Acad Sci U S A 2011; 108:11181–11186.
70. Alvarez RA, Maestre AM, Law K, et al. Enhanced FCGR2A and FCGR3A signaling by HIV viremic controller IgG. JCI Insight 2017; 2:e88226.
71. Bonsignori M, Pollara J, Moody MA, et al. Antibody-dependent cellular cytotoxicity-mediating antibodies
from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family. J Virol 2012; 86:11521–11532.
72. Gomez-Roman VR, Patterson LJ, Venzon D, et al. Vaccine-elicited antibodies
mediate antibody-dependent cellular cytotoxicity correlated with significantly reduced acute viremia in rhesus macaques challenged with SIVmac251. J Immunol 2005; 174:2185–2189.
73. Excler JL, Ake J, Robb ML, et al. Nonneutralizing functional antibodies
: a new ‘old’ paradigm for HIV vaccines
. Clin Vaccine Immunol 2014; 21:1023–1036.
74. Aasa-Chapman MM, Holuigue S, Aubin K, et al. Detection of antibody-dependent complement-mediated inactivation of both autologous and heterologous virus in primary human immunodeficiency virus type 1 infection. J Virol 2005; 79:2823–2830.
75. Spear GT, Landay AL, Sullivan BL, et al. Activation of complement on the surface of cells infected by human immunodeficiency virus. J Immunol 1990; 144:1490–1496.
76. Spear GT, Sullivan BL, Landay AL, Lint TF. Neutralization of HIV-1 by complement occurs by viral lysis. J Virol 1990; 64:5869–5873.
77. Sips M, Krykbaeva M, Diefenbach TJ, et al. Fc receptor-mediated phagocytosis in tissues as a potent mechanism for preventive and therapeutic HIV vaccine strategies. Mucosal Immunol 2016; 9:1584–1595.
78. Ackerman ME, Mikhailova A, Brown EP, et al. Polyfunctional HIV-specific antibody responses are associated with spontaneous HIV control. PLoS Pathog 2016; 12:e1005315.
79▪. Alter G, Dowell KG, Brown EP, et al. High-resolution definition of humoral immune response correlates of effective immunity against HIV. Mol Syst Biol 2018; 14:e7881.
Systemic serological analysis of a cohort of HIV-infected individuals with varying degrees of viral control revealed multifaceted and coordinated contributions of polyclonal antibodies to diverse antiviral responses and suggests key biophysical features predictive of viral control.
80. Forthal DN, Gilbert PB, Landucci G, Phan T. Recombinant gp120 vaccine-induced antibodies
inhibit clinical strains of HIV-1 in the presence of fc receptor-bearing effector cells and correlate inversely with HIV infection rate. J Immunol 2007; 178:6596–6603.
81. Hidajat R, Xiao P, Zhou Q, et al. Correlation of vaccine-elicited systemic and mucosal nonneutralizing antibody activities with reduced acute viremia following intrarectal simian immunodeficiency virus SIVmac251 challenge of rhesus macaques. J Virol 2009; 83:791–801.
82. Florese RH, Demberg T, Xiao P, et al. Contribution of nonneutralizing vaccine-elicited antibody activities to improved protective efficacy in rhesus macaques immunized with Tat/Env compared with multigenic vaccines
. J Immunol 2009; 182:3718–3727.
83. Xiao P, Zhao J, Patterson LJ, et al. Multiple vaccine-elicited nonneutralizing antienvelope antibody activities contribute to protective efficacy by reducing both acute and chronic viremia following simian/human immunodeficiency virus SHIV89.6P challenge in rhesus macaques. J Virol 2010; 84:7161–7173.