Despite extensive efforts, significant gaps remain in our understanding of which host factors promote or restrict human immunodeficiency virus (HIV) infection in human CD4+ T cells. Here, we employed orthogonal genome-wide CRISPR activation (CRISPRa) and CRISPR knockout (CRISPRn) screens in primary CD4+ T cells to discover both pro- and anti-HIV host factors systematically. We used secondary pooled screens and targeted individual CRISPR perturbations to validate high-confidence hits and reveal their diverse mechanisms of action. CRISPRa notably revealed potent antiviral factors, including PI16, PPID, SHISA3, and ITM2A – many of which would have been missed by gene knockout experiments alone. When PI16 is overexpressed in CD4+ T cells, it physically interacts with CD4 and numerous HIV host factors involved in viral fusion, and efficiently inhibits HIV entry. We also discovered another novel antiviral factor, PPID (Cyp40). PPID is a paralog of CypA (or PPIA), which is a proviral factor that regulates nuclear entry kinetics of HIV cores. PPID also binds to HIV capsid, but unlike CypA, it restricts infection by blocking nuclear import of the viral core. Structural modeling, evolutionary analyses, and targeted mutagenesis identified domains and residues that mediate restriction of HIV by PPID, including specific substitutions from non-human primate orthologs that improve HIV restriction. Together, our data systematically define the functional HIV-host interaction landscape in primary human T cells and reveal new mechanisms to modulate infection.