AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 18, Number 8, 2002, pp. 545–556 © Mary Ann Liebert, Inc. Adaptive Changes after Human Immunodeficiency Virus Type 1 Transmission VICTORIA A. LAWSON, 1,2 ROBERT OELRICHS, 3,4 CHRISTOPHE GUILLON, 5,6 ALLISON A. IMRIE, 7,8 DAVID A. COOPER, 7 NICHOLAS J. DEACON, 3 and DALE A. MCPHEE 1 ABSTRACT Primary HIV-1 infection (PHI) is associated with a period of viremia, the resolution of which generally coin- cides with the development of both humoral and cellular immune responses. In this study replication-com- petent quasispecies were derived from virus isolated from an individual before and after seroconversion. Virus was also isolated from the presumed donor. Phenotypic and genotypic analysis of biological clones identified transmission of an R5/M-tropic phenotype. However, the ability of clones derived from the recipient to repli- cate in primary macrophages and PBMCs was restricted after transmission. This apparent selection process was supported by analysis of molecular clones derived from the isolated virus. Analysis of the ratio of syn- onymous and nonsynonymous substitutions predicted the existence of selective pressure soon after transmis- sion, coincident with the development of HIV-1-specific antibodies. An Env trans-complementation assay dem- onstrated that the infectivity of a clone derived from the recipient after seroconversion was enhanced in the presence of a selected neutralizing antibody, indicating that the developing humoral immune response may have at least in part contributed to the selective pressure identified. 545 INTRODUCTION P RIMARY HIV-1 INFECTION (PHI) is associated with a period of viremia, the resolutionof which generallycoincideswith seroconversion 1 and the development of broadly reactive cyto- toxic T lymphocytes. 2–4 A high viral load “set point” and the presence of T-tropic virus after primary infection 5–7 are strong predictorsof disease progression.An understandingof the host factors that influence the establishment of this set point and the rate of disease progression may lead to improved treatment and disease prognosis. Precedence exists for selection of HIV-1 quasi-species during transmission and seroconversion.It has been widely reported that the viral population after transmission is relatively homogeneous and is most commonly composed of the macrophage (M)-tropic or R5 phenotype, 8–12 despite the presence of T-tropic or X4 virus in the donor. 8,13 From studies that have been able to compare the genotype of the virus before and after transmission it is apparent that the transmitted virus often represents a minor donor vari- ant. 8,13,14 In several instances in which a transmitted virus was found to have a T-tropic/X4 phenotype it was replaced by an M- tropic/R5 variant after seroconversion. 15–17 Therefore, primary HIV-1 infection appears to be influenced by two events: The first occurs during the initial transmission event and the second over the period of seroconversion. In this study the availability of virus isolated from an HIV- 1 AIDS Cellular Biology Unit and National Centre in HIV Virology Research, Macfarlane Burnet Institute for Medical Research and Public Health, Fairfield (Melbourne), Victoria, Australia 3078; and Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3052, Australia. 2 Present address: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana 59840. 3 AIDS Molecular Biology Unit and National Centre in HIV Virology Research, Macfarlane Burnet Institute for Medical Research and Pub- lic Health, Fairfield (Melbourne), Victoria, Australia 3078; and Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3052, Australia. 4 Thai Red Cross Society Program on AIDS, Pathumwan, Bangkok, Thailand. 5 Department of Virology, Erasmus University, Rotterdam, The Netherlands. 6 Present address: UMR 2142 CNRS/BioMérieux, ENS Lyon, Lyon, France. 7 Department of Immunology and National Centre for HIV Epidemiology and Clinical Research, Sydney, Australia. 8 Present address: Retrovirology Research Laboratory, University of Hawaii, Leahi Hospital, Honolulu, Hawaii 96816.