Topical Microbicides Become Topical
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《新英格兰医药杂志》
Developing a preventive human immunodeficiency virus type 1 (HIV-1) vaccine that decisively reduces the rate of spread of the AIDS pandemic will take many years, at best. In the meantime, can the scientific community apply other biology-based methods to halt the transmission of HIV-1? A recent study performed by Lederman and colleagues with the use of a nonhuman primate model of sexual transmission indicates that this feat may be possible.1 By applying a specific inhibitor of virus–cell fusion to the vaginal vault of rhesus macaques, Lederman et al. protected the animals against a subsequent challenge by a vaginally inoculated, genetically engineered lentivirus closely related to HIV-1 (a "simian–human immunodeficiency virus," or SHIV).
What implications does this study have for the development of a practical strategy to prevent the transmission of HIV-1 to women? The concept under evaluation is that of a topical microbicide — a vaginally or rectally applied compound designed to inactivate incoming HIV-1, or to prevent the virus from entering or replicating in the cells that it infects, at or near its site of deposition (Figure 1). The idea of a microbicide has been around for over 15 years, but only in recent years has it attracted substantial funding and the attention of the research community.2,3 One factor behind the new interest has been the increasing availability of compounds that are designed specifically to inhibit virus–cell fusion, compounds that are likely to be safe even when applied topically on a regular basis.3 If HIV-1 is prevented from entering cells, it effectively becomes an inert particle.
Figure 1. Possible Actions of a Vaginally Administered Topical Microbicide.
Lederman and colleagues1 applied PSC-RANTES, a synthetic analogue of the chemokine RANTES, to the vaginal walls of macaques. PSC-RANTES binds the chemokine CCR5 coreceptor, thus preventing the entry of a genetically engineered simian–human immunodeficiency virus (SHIV SF162). STDs denotes sexually transmitted diseases.
The particular compound used by Lederman and colleagues is PSC-RANTES, a chemically modified derivative of the natural chemokine RANTES.1 Its target is the CCR5 coreceptor used by the most commonly transmitted strains of HIV-1 to enter CD4+ T cells, macrophages, and some types of dendritic cell — cells that are targets for the virus in or near the vaginal epithelium.3 Applied in the millimolar concentration range, PSC-RANTES protected macaques from the SHIV SF162 virus,1 which gains entry into cells by binding to CCR5. PSC-RANTES itself is not likely to become a practical microbicide for human use. Any final product would have to be safe, effective, user-friendly, and cheap — preferably less than the price of a condom.2,3 The complex manufacturing process required to make and then modify a peptide such as PSC-RANTES is likely to be too expensive to be cost-effective. For much the same reason, HIV-1–specific monoclonal antibodies that also protect macaques from vaginal transmission of SHIV SF162 are unlikely to become a practical microbicide.4 Yet several, much cheaper compounds are now available that also block various stages of the attachment and fusion of virus to cells.2 Alone, and even better in combination, some of these more practical inhibitors can also consistently protect macaques against vaginal transmission of SHIV SF162 (Veazey RS: personal communication).
The macaque model used in these studies is a stringent test of a microbicide. It involves deliberate thinning of the vaginal epithelium through the use of progesterone, which greatly increases the susceptibility of the macaques to infection.1,4 And the dose of virus used is about 100 times the highest recorded in human semen.4,5 So success in this animal model is no trivial matter, and it is a very encouraging sign from the perspective of efficacy in humans. It can be argued that the macaque model is too stringent and that lower concentrations of blocking compounds might be effective in humans. My own view is that we need to be prepared for the worst-case scenario, not the best. A microbicide might have to be able to counter events involving a relatively high probability of transmission to reduce the spread of HIV-1 when it matters most. Viral loads can be extremely high in the blood and semen of men undergoing primary infection, making these men highly infectious and the driving force behind the explosive spread of new, local HIV-1 epidemics.5 It may not be easy for a microbicide to intervene in such circumstances. The presence of other sexually transmitted diseases also greatly increases the risk of transmitting or acquiring HIV-1 infection in humans5; their presence is not allowed for in animal models, but they will surely make the task of a microbicide harder, not easier, in women.
The preclinical, animal-testing stage of the microbicide development process is proceeding very well. The next step is to persuade the pharmaceutical industry to take the microbicide concept seriously. The kinds of compounds that will protect macaques from vaginal infection are similar to ones now being developed as orally available systemic drugs for the treatment of HIV-1 infection. So why not use them topically as well to prevent transmission? For this to happen, funding agencies, microbicide advocacy groups, scientists, and corporations must work together to combine multiple compounds from different companies into a practical product. This goal is possible scientifically and imperative from a public health perspective, but it should not preclude continued efforts to develop a vaccine — the ultimate long-term solution. The various prevention options can be complementary; for example, vaccine antigens could be formulated as a topical microbicide and applied vaginally or rectally to provide partial protection and mucosal immunization simultaneously.
Source Information
From the Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York.
References
Lederman MM, Veazey RS, Offord R, et al. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 2004;306:485-487.
Stone A. Microbicides: a new approach to preventing HIV and other sexually transmitted infections. Nat Rev Drug Discov 2002;1:977-985.
Shattock RA, Moore JP. Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 2003;1:25-34.
Veazey RS, Shattock RJ, Pope M, et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med 2003;9:343-346.
Pilcher CD, Tien HC, Eron JJ Jr, et al. Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis 2004;189:1785-1792.(John P. Moore, Ph.D.)
What implications does this study have for the development of a practical strategy to prevent the transmission of HIV-1 to women? The concept under evaluation is that of a topical microbicide — a vaginally or rectally applied compound designed to inactivate incoming HIV-1, or to prevent the virus from entering or replicating in the cells that it infects, at or near its site of deposition (Figure 1). The idea of a microbicide has been around for over 15 years, but only in recent years has it attracted substantial funding and the attention of the research community.2,3 One factor behind the new interest has been the increasing availability of compounds that are designed specifically to inhibit virus–cell fusion, compounds that are likely to be safe even when applied topically on a regular basis.3 If HIV-1 is prevented from entering cells, it effectively becomes an inert particle.
Figure 1. Possible Actions of a Vaginally Administered Topical Microbicide.
Lederman and colleagues1 applied PSC-RANTES, a synthetic analogue of the chemokine RANTES, to the vaginal walls of macaques. PSC-RANTES binds the chemokine CCR5 coreceptor, thus preventing the entry of a genetically engineered simian–human immunodeficiency virus (SHIV SF162). STDs denotes sexually transmitted diseases.
The particular compound used by Lederman and colleagues is PSC-RANTES, a chemically modified derivative of the natural chemokine RANTES.1 Its target is the CCR5 coreceptor used by the most commonly transmitted strains of HIV-1 to enter CD4+ T cells, macrophages, and some types of dendritic cell — cells that are targets for the virus in or near the vaginal epithelium.3 Applied in the millimolar concentration range, PSC-RANTES protected macaques from the SHIV SF162 virus,1 which gains entry into cells by binding to CCR5. PSC-RANTES itself is not likely to become a practical microbicide for human use. Any final product would have to be safe, effective, user-friendly, and cheap — preferably less than the price of a condom.2,3 The complex manufacturing process required to make and then modify a peptide such as PSC-RANTES is likely to be too expensive to be cost-effective. For much the same reason, HIV-1–specific monoclonal antibodies that also protect macaques from vaginal transmission of SHIV SF162 are unlikely to become a practical microbicide.4 Yet several, much cheaper compounds are now available that also block various stages of the attachment and fusion of virus to cells.2 Alone, and even better in combination, some of these more practical inhibitors can also consistently protect macaques against vaginal transmission of SHIV SF162 (Veazey RS: personal communication).
The macaque model used in these studies is a stringent test of a microbicide. It involves deliberate thinning of the vaginal epithelium through the use of progesterone, which greatly increases the susceptibility of the macaques to infection.1,4 And the dose of virus used is about 100 times the highest recorded in human semen.4,5 So success in this animal model is no trivial matter, and it is a very encouraging sign from the perspective of efficacy in humans. It can be argued that the macaque model is too stringent and that lower concentrations of blocking compounds might be effective in humans. My own view is that we need to be prepared for the worst-case scenario, not the best. A microbicide might have to be able to counter events involving a relatively high probability of transmission to reduce the spread of HIV-1 when it matters most. Viral loads can be extremely high in the blood and semen of men undergoing primary infection, making these men highly infectious and the driving force behind the explosive spread of new, local HIV-1 epidemics.5 It may not be easy for a microbicide to intervene in such circumstances. The presence of other sexually transmitted diseases also greatly increases the risk of transmitting or acquiring HIV-1 infection in humans5; their presence is not allowed for in animal models, but they will surely make the task of a microbicide harder, not easier, in women.
The preclinical, animal-testing stage of the microbicide development process is proceeding very well. The next step is to persuade the pharmaceutical industry to take the microbicide concept seriously. The kinds of compounds that will protect macaques from vaginal infection are similar to ones now being developed as orally available systemic drugs for the treatment of HIV-1 infection. So why not use them topically as well to prevent transmission? For this to happen, funding agencies, microbicide advocacy groups, scientists, and corporations must work together to combine multiple compounds from different companies into a practical product. This goal is possible scientifically and imperative from a public health perspective, but it should not preclude continued efforts to develop a vaccine — the ultimate long-term solution. The various prevention options can be complementary; for example, vaccine antigens could be formulated as a topical microbicide and applied vaginally or rectally to provide partial protection and mucosal immunization simultaneously.
Source Information
From the Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York.
References
Lederman MM, Veazey RS, Offord R, et al. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 2004;306:485-487.
Stone A. Microbicides: a new approach to preventing HIV and other sexually transmitted infections. Nat Rev Drug Discov 2002;1:977-985.
Shattock RA, Moore JP. Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 2003;1:25-34.
Veazey RS, Shattock RJ, Pope M, et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med 2003;9:343-346.
Pilcher CD, Tien HC, Eron JJ Jr, et al. Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis 2004;189:1785-1792.(John P. Moore, Ph.D.)