Despite effective anti retroviral therapy, a cure for HIV remains elusive. Lentiviral gene therapy can be used to deliver protective genes into target cells thus rendering them resistant to HIV. Current lentiviral vectors are unable to efficiently transduce target populations due to lower fusogenic capacity of vector envelopes and restriction of reverse transcription (RT) in resting immune cells especially resting CD4 T cells. To increase the fusogenic capacity of lentiviral vectors for CD4 T cells, we short-listed 10 lead HIV envelopes based on their ability to use high levels of CD4 from a repository of over 1000 envelopes characterised using the HIV Affinofile assay. To increase reverse transcription in resting cells, we screened a panel of genetically diverse Vpx variants for their ability to i) initially enhance HIV NL43 infection and ii) increase gene delivery using modified lentiviral vectors. Using this approach, HIV envelope sequences were identified with fusogenic potential of greater than 90% for resting memory and naïve T cells. Our studies in macrophages showed that incorporation of Vpx from SIVmac239 into lentiviral vectors led to a significant increase in lentiviral transduction by enhancing lentiviral RT and integration kinetics. Our diverse Vpx screens revealed that not all variants enhanced transductions equally, with cell specific differences observed between macrophages and resting T cells. Majority of Vpx variants enhanced gene delivery and HIV infection over 14 days, and this directly led to antagonism of vectors that mediate HIV gene silencing. Importantly we identified one Vpx variant that lacked this antagonism due to its ability to enhance gene delivery in the short term. Herein we have identified a gene delivery pipeline for resting T cells that leverages the fusogenic potential of HIV-1 and the enhancing potential of Vpx.