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Caution required in developing HIV vaccine
Medical Hypofhem @I Lmgman
(1990) 31.155-156 Ltd 19%
Group UK
Caution Required in Developing
HIV Vaccine
M. RABINOFF Department
of Biology,
University
of Tennessee,
Chattanooga,
Recently, experimental evidence has been presented for antibody dependent enhancement of HIV infection (which may have been directed against a portion of gp160) (1). Concerns about antibodies directed against gp120 (the external portion of the HIV envelope glycoprotein) and gp160 (the whole HIV envelope gene product, containing gp120 and gp41, the transmembrane portion) derived vaccines have also been expressed (2). There are several major concerns about gp120 derived vaccines. The carboxyl terminal region of the PE3 region of gp120 residues 238 to 282) contains a conserved area that is 31% homologous (with 73% alignment when chemically similar and evolutionary replacements of amino acids are considered) to neuroleukin (which itself may be identical to glucophosphoisomerase (3)). Neuroleukin is a factor involved in nerve cell growth (it promotes the survival in culture of embryonic spinal neurons that probably includes skeletal motor neurons, as well as cultured sensory neurons) and with lymphokine action (acting as a lectin stimulated T cell product that induces polyclonal B-cell maturation to immunoglobin secretion). It has been shown that gp120, or the PEX region, in in vitro experiments adversely affects nerve growth. This might occur in vivo, and thus account for at least some of the neurological impairment (i.e. AIDS dementia) seen with HIV infection (4); however, such adverse neurological effects have not at present
TN., 37403, USA
been demonstrated in in vivo experiments. It is thus possible that the antibodies produced by a vaccine that attach to the gp120. region of the virus might also attach to neuroleukin in the body. This could potentially affect neuroleukin metabolism and prevent its action in the body. This may be an especially important issue for vaccinated women who become pregnant or are breastfeeding, since the vaccine will produce IgG antibodies that can cross the placenta and could possibly affect neuroleukin in the fetus; this could potentially affect the neurological development of the fetus severely (neuroleukin is known to affect early neurological development). Maternal antibodies, as part of the passive immunity process, could enter the newborn infant through breastfeeding, and cause similar damage. Another area of concern involves the binding of gp120 to the CD4 receptor (present on T helper cells, some B cells, mononuclear phagocytes, dendritic and Langerhans cells, and neutral giial cells) or other receptors on CD4+ cells. It has been suggested that gp120 that has been expressed from infected cells might attach to healthy cells not infected by the virion, and be involved in antibody dependent cellular cytotoxicity (ADCC) or natural killer (NK) cell attack, thus diminishing the population of healthy CD4 bearing cells, and that this phenomenon may be important in HIV infection pathogenesis (5). Thus, while antibodies developed against various regions of gp120 might block binding of 15.5
MEDICAL
156 HIV to CD4, or otherwise neutralize the virus, they might also set up attack on the healthy CD4 bearing cells in HIV infected individuals. Areas of gp120 that affect binding or fusion to CD4 bearing cells include residues 397-439, with deletion of residues 410-421 completely blocking binding; antibodies to the RP235 region (residues 307-330) completely block fusion, but not binding; and an eight amino acid sequence, called Peptide T (residues 193-200), has been shown to be involved in binding to brain membranes and in HIV infection of T cells. In both non-infected and infected individuals, such vaccine derived antibodies might attach to chemicals that normally bind to the CD4 receptor or other immunologically important receptors, thus causing deficient cellular immune function (2). As an example, mutations introduced into, and antibodies directed against, a conserved ten amino acid sequence (residues 261 to 270) of gp120 have been shown to block infectivity without affecting virus binding to the CD4 receptor. It has recently been noted that this region is very homologous (70% plus one additional conservative change) to a ten amino acid region in the extracellular membrane proximal domain of HLA class II beta-chains (region 142 to 151 of the consensus -DR, -DP and -DQ beta chain) (6). While it is extremely important to develop a vaccine to prevent and possibly treat HIV infec-
HYPOTHESES
tion, there is ample reason to have concern about the possible adverse effects of such vaccines. Further work needs to be done to elucidate which viral antigens might be involved in antibody deenhancement in HIV infection, pendent especially if that phenomenon is found to be important in HIV pathogenesis. Also, further work needs to be done to determine the effects of various regions in gp120 or gp160, and if antibodies developed against these regions will have adverse neurological and/or cellular immune effects.
References 1. Robinson 2. 3.
4.
5.
6.
W. Montefiori D. Mitchell W. Will antibodydependent enhancement of HIV-1 infection be a problem with AIDS vaccines? Lancet 1: 830-l. 1988. Barnes D. Solo actions of AIDS virus coat. Science 237: 971-3, 1987. Faik P, Walker .I. Redmill A. Morgan M. Mouse glucose6-phosphate isomerase and neuroleukin have identical 3’ sequences. Nature 332: 4.5-7, 1988. Lee M, Gurney M. Functional interaction and partial homology between human immunodeficiency virus and neuroleukin. Science 237: 1047-51. 1987. Lyerly H, Matthews T. Langlois A, Bolognesi D. Weinhold K. Human T cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack. Proc Nas Acad Sci 84: 4601-5, 1987. Young J. HIV and HLA similarity. Nature 333: 215, 1988.
(1990) 31.155-156 Ltd 19%
Group UK
Caution Required in Developing
HIV Vaccine
M. RABINOFF Department
of Biology,
University
of Tennessee,
Chattanooga,
Recently, experimental evidence has been presented for antibody dependent enhancement of HIV infection (which may have been directed against a portion of gp160) (1). Concerns about antibodies directed against gp120 (the external portion of the HIV envelope glycoprotein) and gp160 (the whole HIV envelope gene product, containing gp120 and gp41, the transmembrane portion) derived vaccines have also been expressed (2). There are several major concerns about gp120 derived vaccines. The carboxyl terminal region of the PE3 region of gp120 residues 238 to 282) contains a conserved area that is 31% homologous (with 73% alignment when chemically similar and evolutionary replacements of amino acids are considered) to neuroleukin (which itself may be identical to glucophosphoisomerase (3)). Neuroleukin is a factor involved in nerve cell growth (it promotes the survival in culture of embryonic spinal neurons that probably includes skeletal motor neurons, as well as cultured sensory neurons) and with lymphokine action (acting as a lectin stimulated T cell product that induces polyclonal B-cell maturation to immunoglobin secretion). It has been shown that gp120, or the PEX region, in in vitro experiments adversely affects nerve growth. This might occur in vivo, and thus account for at least some of the neurological impairment (i.e. AIDS dementia) seen with HIV infection (4); however, such adverse neurological effects have not at present
TN., 37403, USA
been demonstrated in in vivo experiments. It is thus possible that the antibodies produced by a vaccine that attach to the gp120. region of the virus might also attach to neuroleukin in the body. This could potentially affect neuroleukin metabolism and prevent its action in the body. This may be an especially important issue for vaccinated women who become pregnant or are breastfeeding, since the vaccine will produce IgG antibodies that can cross the placenta and could possibly affect neuroleukin in the fetus; this could potentially affect the neurological development of the fetus severely (neuroleukin is known to affect early neurological development). Maternal antibodies, as part of the passive immunity process, could enter the newborn infant through breastfeeding, and cause similar damage. Another area of concern involves the binding of gp120 to the CD4 receptor (present on T helper cells, some B cells, mononuclear phagocytes, dendritic and Langerhans cells, and neutral giial cells) or other receptors on CD4+ cells. It has been suggested that gp120 that has been expressed from infected cells might attach to healthy cells not infected by the virion, and be involved in antibody dependent cellular cytotoxicity (ADCC) or natural killer (NK) cell attack, thus diminishing the population of healthy CD4 bearing cells, and that this phenomenon may be important in HIV infection pathogenesis (5). Thus, while antibodies developed against various regions of gp120 might block binding of 15.5
MEDICAL
156 HIV to CD4, or otherwise neutralize the virus, they might also set up attack on the healthy CD4 bearing cells in HIV infected individuals. Areas of gp120 that affect binding or fusion to CD4 bearing cells include residues 397-439, with deletion of residues 410-421 completely blocking binding; antibodies to the RP235 region (residues 307-330) completely block fusion, but not binding; and an eight amino acid sequence, called Peptide T (residues 193-200), has been shown to be involved in binding to brain membranes and in HIV infection of T cells. In both non-infected and infected individuals, such vaccine derived antibodies might attach to chemicals that normally bind to the CD4 receptor or other immunologically important receptors, thus causing deficient cellular immune function (2). As an example, mutations introduced into, and antibodies directed against, a conserved ten amino acid sequence (residues 261 to 270) of gp120 have been shown to block infectivity without affecting virus binding to the CD4 receptor. It has recently been noted that this region is very homologous (70% plus one additional conservative change) to a ten amino acid region in the extracellular membrane proximal domain of HLA class II beta-chains (region 142 to 151 of the consensus -DR, -DP and -DQ beta chain) (6). While it is extremely important to develop a vaccine to prevent and possibly treat HIV infec-
HYPOTHESES
tion, there is ample reason to have concern about the possible adverse effects of such vaccines. Further work needs to be done to elucidate which viral antigens might be involved in antibody deenhancement in HIV infection, pendent especially if that phenomenon is found to be important in HIV pathogenesis. Also, further work needs to be done to determine the effects of various regions in gp120 or gp160, and if antibodies developed against these regions will have adverse neurological and/or cellular immune effects.
References 1. Robinson 2. 3.
4.
5.
6.
W. Montefiori D. Mitchell W. Will antibodydependent enhancement of HIV-1 infection be a problem with AIDS vaccines? Lancet 1: 830-l. 1988. Barnes D. Solo actions of AIDS virus coat. Science 237: 971-3, 1987. Faik P, Walker .I. Redmill A. Morgan M. Mouse glucose6-phosphate isomerase and neuroleukin have identical 3’ sequences. Nature 332: 4.5-7, 1988. Lee M, Gurney M. Functional interaction and partial homology between human immunodeficiency virus and neuroleukin. Science 237: 1047-51. 1987. Lyerly H, Matthews T. Langlois A, Bolognesi D. Weinhold K. Human T cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack. Proc Nas Acad Sci 84: 4601-5, 1987. Young J. HIV and HLA similarity. Nature 333: 215, 1988.