The immune response during acute HIV-1 infection: clues for vaccine development Andrew J. McMichael, Persephone Borrow, Georgia D. Tomaras, Nilu Goonetilleke, Barton F. Haynes Abstract: The early immune response to HIV-1 infection is likely to be an important factor in determining the clinical course of disease. Recent data indicate that the HIV-1 quasispecies that arise following a mucosal infection are usually derived from a single transmitted virus. Moreover, the finding that the first effective immune responses drive the selection of virus escape mutations provides insight into the earliest immune responses against the transmitted virus and their contributions to the control of acute viraemia. Strong innate and adaptive immune responses occur subsequently but they are too late to eliminate the infection. In this Review, we discuss recent studies on the kinetics and quality of early immune responses to HIV-1 and their implications for developing a successful preventive HIV-1 vaccine. Viral set point: The time at which plasma viraemia settles to a stable level (within approximately 3–6 months from the onset of HIV infection). Viral set point is partially predictive of both how quickly HIV infection will progress and the risk of HIV transmission. Recent advances that enable the identification of patients within the first few weeks of HIV-1 infection have provided researchers access to samples from acutely infected patients earlier and in higher numbers than previously available. This has advanced our understanding of the nature of the transmitted virus and the first immune responses in the period before establishment of stable viraemia (the viral set point), which occurs 3–6 months after infection. The first weeks following HIV-1 transmission are extremely dynamic: they are associated with rapid damage to generative immune cell microenvironments, caused by direct viral cytopathicity and bystander effects, and with immune responses that partially control the virus. In this Review, we focus our discussion on the early host or viral factors that are crucial for determining the outcome of HIV-1 infection. These include the nature of the transmitted virus, or founder virus, suppression of the initial infection by genetically influenced immune responses, and the rate of virus mutation and viral fitness of selected mutants. In addition, we review what is known about the nature of innate and adaptive immune responses during this early phase of infection, drawn from studies of humans and macaques infected with HIV-1 and simian immunodeficiency virus (SIV), respectively. Finally, we discuss how our knowledge of the events of early HIV-1 infection can improve the design of a preventive vaccine. The biology of early HIV-1 infection: Transmission. Most HIV-1 infections occur by sexual exposure through the genital tract or rectal mucosa. Although it is not possible to study the very first events following HIV-1 transmission in humans in vivo, we have gained some understanding from studies in which mucosal tissue explants were infected in vitro. Further understanding of the first stages of infection in vivoThe immune response during acute HIV-1 infection: clues for vaccine development Andrew J. McMichael, Persephone Borrow, Georgia D. Tomaras, Nilu Goonetilleke, Barton F. Haynes Abstract: The early immune response to HIV-1 infection is likely to be an important factor in determining the clinical course of disease. Recent data indicate that the HIV-1 quasispecies that arise following a mucosal infection are usually derived from a single transmitted virus. Moreover, the finding that the first effective immune responses drive the selection of virus escape mutations provides insight into the earliest immune responses against the transmitted virus and their contributions to the control of acute viraemia. Strong innate and adaptive immune responses occur subsequently but they are too late to eliminate the infection. In this Review, we discuss recent studies on the kinetics and quality of early immune responses to HIV-1 and their implications for developing a successful preventive HIV-1 vaccine. Viral set point: The time at which plasma viraemia settles to a stable level (within approximately 3–6 months from the onset of HIV infection). Viral set point is partially predictive of both how quickly HIV infection will progress and the risk of HIV transmission. Recent advances that enable the identification of patients within the first few weeks of HIV-1 infection have provided researchers access to samples from acutely infected patients earlier and in higher numbers than previously available. This has advanced our understanding of the nature of the transmitted virus and the first immune responses in the period before establishment of stable viraemia (the viral set point), which occurs 3–6 months after infection. The first weeks following HIV-1 transmission are extremely dynamic: they are associated with rapid damage to generative immune cell microenvironments, caused by direct viral cytopathicity and bystander effects, and with immune responses that partially control the virus. In this Review, we focus our discussion on the early host or viral factors that are crucial for determining the outcome of HIV-1 infection. These include the nature of the transmitted virus, or founder virus, suppression of the initial infection by genetically influenced immune responses, and the rate of virus mutation and viral fitness of selected mutants. In addition, we review what is known about the nature of innate and adaptive immune responses during this early phase of infection, drawn from studies of humans and macaques infected with HIV-1 and simian immunodeficiency virus (SIV), respectively. Finally, we discuss how our knowledge of the events of early HIV-1 infection can improve the design of a preventive vaccine. The biology of early HIV-1 infection: Transmission. Most HIV-1 infections occur by sexual exposure through the genital tract or rectal mucosa. Although it is not possible to study the very first events following HIV-1 transmission in humans in vivo, we have gained some understanding from studies in which mucosal tissue explants were infected in vitro. Further understanding of the first stages of infection in vivo