Vol 348 • September 7, 1996 631 THE LANCET COMMENTARY AIDS—beyond helper T cells See page 649 The inexorable decline in the numbers of CD4 T cells and its association with the loss of cell-mediated immunity are major hallmarks of advancing AIDS. One of the most important observations in the study of HIV type- 1 (HIV-1) was that the virus infected CD4 helper cells and used the CD4 molecule as a receptor for entry. This finding provided a convincing hypothesis—CD4 T cells become infected via their CD4 receptors and are lost by lytic infection or destruction by CD8 killer T cells. The disturbing fact that only a small proportion of CD4 T cells was infected in the peripheral blood pool could, perhaps, be dismissed because efficient destruction of a population of infected cells would leave few infected survivors, an idea supported by the high turnover rate of infected CD4 cells. 1 However, a decade of research following the description of CD4 as a receptor for HIV has testified that the pathogenesis of the infection is not that simple and that infection of other cell types may contribute to pathogenesis. The paper published this week confirms infection of immunologically important cell types other than CD4 T cells—namely, CD8 cells and dendritic antigen-presenting cells. In individuals with CD4 counts below 200/μL most infected cells were either dendritic cells or CD8 lymphocytes. What is the significance of infection of these other cell types? It is first necessary to understand the part played by CD8 T cells and dendritic cells in HIV infection. For CD8 T cells controversy rages as to whether these cells are beneficial or detrimental. On the plus side, increasing numbers of individuals who are exposed to HIV and remain seronegative—particularly some Gambian prostitutes who have repeated exposure—have cell- mediated immunity to HIV, including the presence of CD8 cytotoxic T lymphocytes. 2 High counts of CD8 cytotoxic T cells are also present in symptom-free individuals and may be lost with progression to AIDS. CD8 T cells also produce soluble products that can block HIV infection, 3 and among these are the chemokines macrophage inhibitory proteins MIP-1alpha and MIP-1ß and RANTES. These factors bind and block one of the recently identified co-receptors (with CD4) for viral entry into cells (CC-CKR-5). However, in animal models of immunosuppressive viral diseases, CD8 cytotoxic T lymphocyte activity has been associated with pathological findings. In particular, killer T cells may remove dendritic cells that are responsible for acquiring and presenting the antigen to T cells to initiate immune responses. 4 The debate thus continues as to whether CD8 killer T cells may be vital to the development of protective immunity or conversely responsible for pathological sequelae. As generally happens, the truth could lie somewhere between these two situations. Early in disease in the presence of low viral loads, an efficient clearance of virus-infected cells by CD8 T cells may be beneficial. With high virus loads, perhaps maintained through cycles of latent and productive infection, CD8 T cells might remove vital components of the immune response. 4 The infection of CD8 T cells now identified as part of this scenario may help to define their importance in protection or pathogenesis. If the increased infection of CD8 T cells is a late feature, then the infection of antigen-presenting dendritic cells may occur earlier. 5 Langerhans’ cells (dendritic cells in the skin and in genital mucosa) could be the earliest cells infected with retrovirus. These cells are specialised to acquire and process antigens in the periphery, to carry them to draining lymph nodes, and to cluster and activate antigenically naive T cells located in the lymph nodes. These properties are not found in other cell types. Infection of mucosal dendritic cells and transmission of virus to T cells during their activation within the draining lymph nodes may be the initial route of infection. There is a greater susceptibility of Langerhans’ cells to infection with the clades of HIV prevalent in Asia and sub-Saharan Africa than to viruses circulating in Europe or in the United States. 6 This greater susceptibility has been proposed to be a mechanism underlying the greater ease of heterosexual transmission of the former viruses. Dendritic cells also become reduced in number and lose their capacity to stimulate T-cell proliferation, even in symptomless infection. By contrast, they maintain the capacity to fuel antibody production. Signalling by dendritic cells could thus underlie these two early features of HIV- related disease—loss of T cell-mediated responses and persistence of antibody production. 5 Confirmation that these two cell types, CD8 T cells and dendritic cells, become infected now lends urgency to assessment of the clinical impact of these observations. The prospective measurement of numbers and infection of CD8 T cells and dendritic cells during disease progression and treatment of patients may provide new surrogate disease markers. Infections of both cell types are likely to have consequences ultimately for the management and treatment of patients. As is so often the case with new observations more studies in these areas will be required to define these possibilities precisely. Stella C Knight, Steven Patterson Antigen Presentation Research Group, Imperial College School of Medicine at Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, UK 1 Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. N ature 1995; 373 123–26. 2 Rowland-Jones SL, McMichael A. Immune responses in HIV-exposed seronegatives: have they repelled the virus? Curr Opin Immunol 1995; 7: 448–55. 3 Levy JA, Mackewicz CE, Barker E. Controlling HIV pathogenesis: the role of the noncytotoxic anti-HIV response of CD8 + T cells. Immunol Today 1996; 17: 217–24. 4 Zinkernagel RM. Are HIV-specific CTL responses salutary or pathogenic? Curr Opin Immunol 1995; 7: 462–70. 5 Knight SC. Bone-marrow-derived dendritic cells and the pathogenesis of AIDS. AIDS 1996; 10: 807–17. 6 Soto-Ramirez LE, Renjifo B, McLane MF, et al. HIV-1 Langerhans cell tropism associated with heterosexual transmission of HIV. S cience 1996; 271: 1291–93. Virus budding from the veil of a dendritic antigen-presenting cell (x11 250, reduced by about half)