One of the earliest markers in the progression of HIV-1 infection was the presence of NEF in the viral strain. NEF is a 27-34 D myrisolated protein unique to primate lente viruses. A functional NEF protein is important for the development of high viremia and AIDS in simian immuodeficiency virus (SIV) in infected rhesus macaques. An important observation first noted in the macaques and later in humans was that animals infected with NEF-deleted virus were resistant to subsequent challenge with pathogenic wild-type viruses. This was followed by the observation in humans that some individuals with long-term non-progressive HIV-1 infection (persons who showed no clinical or immunological signs of immunodeficiency despite being HIV seropositive for over a decade) turn out to be infected with viruses carrying deletion in their NEF gene.