Most cases of primary HIV infection are thought to involve HIV binding initially to the CD4 and CCR5 receptors found on antigen presenting cells which include macrophages, Langerhans' cells, and dendritic cells in the genital and rectal mucosa.

The most widely accepted model for the sexual transmission of HIV is based on infection of the genital tract of rhesus macaques with simian immunodeficiency virus. After female macaques are inoculated intravaginally with simian immunodeficiency virus, the virus targets the Langerhans' cells located in the vaginal mucosa. Once infected, these cells fuse with adjacent CD4 lymphocytes and migrate to deeper tissues. Within two days of infection, the virus can be detected in the internal iliac lymph nodes and shortly thereafter in systemic lymph nodes. This ultimately leads to a fatal infection.

Infection in male macaques occurs when the penile urethra or foreskin is inoculated with simian immunodeficiency virus; the same sequence of cellular events involving the infection of Langerhans' cells is then likely to occur. Infected Langerhans' cells have also been detected in the penile mucosa of male rhesus macaques that have chronic simian immunodeficiency virus infection. In humans, histological studies have identified antigen-presenting cells in the mucosa of the inner foreskin and urethra. Therefore it seems likely that antigen-presenting cells at these mucosal sites are the primary target for HIV in men.

Test tube studies have shown that the CD4 receptor is generally necessary, although insufficient on its own, to permit HIV-1 to enter host cells. The entry of HIV-1 into cells requires an additional chemokine receptor, usually CCR5, although CXCR4 is used by cells that become infected during the later stages of the disease.

After primary infection occurs, the virus mutates, which allows it to utilise other chemokine receptors, such as CXCR4, and thus spread to a variety of cell types.