The dinucleotide CpG is highly underrepresented in the genome of human immunodeficiency virus type 1 (HIV-1). To identify the source of CpG depletion in the HIV-1 genome, we investigated two biological mechanisms: (1) CpG methylation-induced transcriptional silencing and (2) CpG recognition by Toll-like receptors (TLRs). We hypothesized that HIV-1 has been under selective evolutionary pressure by these mechanisms leading to the reduction of CpG in its genome. A CpG depleted genome would enable HIV-1 to avoid methylation-induced transcriptional silencing and/or to avoid recognition by TLRs that identify foreign CpG sequences. We investigated these two hypotheses by determining the sequence context dependency of CpG depletion and comparing it with that of CpG methylation and TLR recognition.We found that in both human and HIV-1 genomes the CpG motifs flanked by T/A were depleted most and those flanked by C/G were depleted least. Similarly, our analyses of human methylome data revealed that the CpG motifs flanked by T/A were methylated most and those flanked by C/G were methylated least. Given that a similar CpG depletion pattern was observed for the human genome within which CpGs are not likely to be recognized by TLRs, we argue that the main source of CpG depletion in HIV-1 is likely host-induced methylation. Analyses of CpG motifs in over 100 viruses revealed that this unique CpG representation pattern is specific to the human and simian immunodeficiency viruses.