<p>Some nucleases may be programmed to break just certain portions of DNA; examples of such enzymes include zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). Insertions and deletions are used by cellular machinery to repair damaged DNA. By specifically targeting long terminal repeats (LTRs), zinc-finger nucleases (ZFNs) efficiently and accurately remove HIV-1 proviral DNA from inactive human T cells, offering a new and different way to eradicate HIV-1 infections. This paper examines the potential, evaluates the current situation, and draws attention to the challenges surrounding the use of TALENs and ZFNs as therapeutic tools for the treatment of HIV infection, to mitigate the adverse off-target effects that result from their extended expression. There is less off-target editing and higher success in targeting HIV escape mutations using TALENs and ZFNs than with CRISPR/Cas-9. The use of ZFNs and TALEN has resulted in changes to many host genes. These include the entrance receptors CCR5 and CXCR4, as well as the proviral integration protein LEDGF/p75. One of the viral targets is the big terminal repeats of proviral DNA. The advancement of gene therapy from the laboratory to the clinic is hindered by the need to reduce immunogenicity, cytotoxicity, and off-target editing while simultaneously enhancing cleavage efficiency and dispersion. However, TALENs technology and breakthroughs in ZFNs are making cleavage more efficient and selective. The strategy for treating HIV might be drastically changed, and maybe even eradicated, by the creation of synthetic nucleases like ZFNs and TALENs. This review explores the current developments about ZFNs and TALENs for the treatment of HIV.</p>