**5. Conclusion**

The pathogenesis of HIV infection is a highly complex network of interconnected processes. It likely borrows much of its complexity from the co-evolution with several mammalian species that HIV and predecessors lentiviruses have enjoyed over an unknown, but rather long period of time. During the complex interplay between HIV and host cell, different intrinsic cell factors are involved that mitigate or restrict HIV replication and spread as shown in Figure 3. Some of these host restrictions factors that have been identified inhibit early steps of replication cycle. In fact, the post-entry step of HIV-1 replication cycle appears to be quite vulnerable to the actions of IFN-inducible restriction factors: TRIM5α, APOBEC3 proteins, SAMHD1 and, more recently, MxB and cholesterol 25-hydroxylase, all of them use distinct mechanisms to prevent integration of viral DNA into host genome. The best characterized of these are the TRIM5α and the APOBEC3 proteins. APOBEC3 interacts with the nascent DNA during reverse transcription while TRIM5α interacts with incoming viral capsids resulting in premature disassembly. SAMHD1 protein acts prior to integration, by depleting the intracellular pool of deoxynucleoside triphosphates (dNTP), therefore impairing HIV-1 reverse transcription and accumulation of HIV double stranded DNA. Another restriction factor, Tetherin (BST- 2/ CD317), acts in late steps of viral replication cycle, by preventing viruses from leaving the cell during budding and release of viral particles. The recently described factors MxB and choles‐ terol 25-hydroxylase seem to inhibit the nuclear import/integration of viral DNA and the viral fusion events, respectively. Remarkably, despite this array of restriction factors, HIV had created viral proteins to subdue these restrictions emphasizing how well adapted this virus is to human host.

**Figure 3. Schematic representation of a simplified replication cycle of HIV and the different steps that are blocked by cellular restriction factors**. The cholesterol-25-hydroxylase blocks viral fusion with target cell membrane; TRIM5α, SAMHD1 and APOBEC3G impair viral DNA synthesis either by accelerating capsid disintegration, reducing dNTPs

intracellular pool or by introducing mutations in nascent chain of viral DNA; MxB impairs the nuclear import and/or the integration step; and finally, Tetherin induces virion retention at the host-cell membrane.

Finally, the identification of cellular restriction factors, such as those referred in this chapter, and the disclosure of the mechanisms by which they impede viral replication, also enabled the identification of new promising targets for therapeutic intervention. In fact, it is increasingly clear that the most successful treatment and/or prevention strategies will likely be derived from the modulation of human cell functions rather than acting directly upon viral mecha‐ nisms.
