Acute HIV infection is characterized by uncontrolled viremia and rapid depletion of CD4+ and CD4- cell subsets. Cell depletion is a cascade of direct virus cytopathicity, immune activation and FasL-dependent cell death that remodels the immune system and allows the establishment of persistent infection. Among the cell subsets that are impacted during acute infection are the γδ T and NK cells. These subsets have overlapping functions for secreting Type 1 cytokines (TNFα and IFNγ), direct cytolysis of infected cells and indirect cell killing through antibody-dependent cellular cytotoxicity (ADCC). Effector cells from both subsets are characterized by expression of CD56 and NKG2D. The acute loss of CD56+ γδ T and NK cells may be linked through cell regulatory networks controlled by costimulatory molecules including 4-1BB, and it is possible that a single event leads to changes in both lymphocyte populations. We also noted a strong correlation between HIV acquisition and high activity alleles of the FCGR3A genes (Fc receptor γIIIa), suggesting that natural antibody may have a role in signaling these innate immune cells and triggering the events of cell depletion. The loss of potent ADCC effector subsets during acute HIV disease, will prevent nascent, HIV-specific antibodies from attacking infected cells and slowing virus spread. Decreased levels of pro-inflammatory cytokines TNFα and IFNγ, will lower the effectiveness of cellular immunity. The impact of HIV infection to debilitate innate immune responses and blunt the effectiveness of virus-specific acquired immunity, reveals a complex mechanism for immune evasion and the establishment of persistent infection. Persons with natural control of viremia do not have γδ T or NK cell defects and this difference accounts in part, for their ability to avoid progressing disease.