Current arguments for the role of cofactors in the initiation of a chronic HIV infection and progression of AIDS are given. The natural history of an HIV infection as affected by cofactors which provide additional stimulatory signals is explored through a mathematical model. The model demonstrates that "antigen load" plays a role in determining susceptibility to an HIV infection. It also suggests that certain individuals may not be able to be infected by small doses of HIV and that the identification and treatment of existing cofactors may be useful in treating early stages of HIV infection. Prevention of cofactor exposures may also protect against HIV infection.