Critical to human innate immunity against African trypanosomes are a minor subclass of human high-density lipoproteins, termed Trypanosome Lytic Factors (TLF). Examination of these particles revealed two subsets termed TLF-1 and TLF-2 based on protein and lipid composition. The TLF-1 molecule binds to a haptoglobin-hemoglobin receptor (HpHbR) on the surface of susceptible trypanosomes, initiating a lytic pathway. T. b. gambiense, which is split into two groups 1 and 2 based on genetic diversity, causes 97% of all cases of African sleeping sickness, a fatal disease of sub-Saharan Africa. Understanding how T. b. gambiense overcomes these factors and infects humans is of major importance in the fight against this disease. Group 1 Trypanosoma brucei gambiense causes human African Trypanosomiasis (HAT), escaping TLF-1 killing due to reduced uptake. Previously, it was identified that, when compared to wild type T. b. brucei, group 1 T. b. gambiense HpHbR (TbgHpHbR) mRNA levels were greatly reduced and the gene contained substitutions within the open reading frame. Here I show that a single, highly conserved amino acid in the TbgHpHbR ablates high affinity TLF-1 binding and subsequent endocytosis, thus evading TLF-1 killing. In addition, we show that over-expression of TbgHpHbR failed to rescue TLF-1 susceptibility. These findings suggest that the single amino acid substitution present in the TbgHpHbR directly contributes to the reduced uptake and resistance to TLF-1 seen in these important human pathogens. These finding indicate that a failure to take up TLF-1 in T. b. gambiense contributes to resistance to TLF-1, although another mechanism is required to overcome TLF-2. Here, in collaboration with Dr. Annette MacLeod, we have examined a T. b. gambiense specific gene, TgsGP, which had previously been suggested to be involved in serum resistance. We show that TgsGP is essential for resistance to lysis as deletion of TgsGP in T. b. gambiense renders the parasites sensitive to human serum as well as recombinant APOL1. Deletion of TgsGP in T. b. gambiense modified to uptake TLF-1 showed sensitivity to TLF-1, APOL1 and human serum. Reintroducing TgsGP into knockout parasite lines restored resistance. The data suggests that TgsGP is essential for human serum resistance in T. b. gambiense.