A lot of the work is done by high throughput screening for drug design, or using biochemistry to design drugs at the atomic level and understand how mutation avoids inhibition. The trouble is that the enzymes are quite similar to human enzymes so the toxicity of high. Some drugs (protease inhibitors and a few reverse transcriptase inhibitors) can be non-toxic but aren't enough on their own and are overcome by mutation. The difficulty is producing something powerful enough to inhibit the viral mechanisms without interfering with host enzymes and be difficult to avoid by mutation. The reason why combination therapy is effective is because if a mutation occurs to render one or two drugs ineffective the remaining drugs will still have an effect and prevent the mutation propergating. Downide if that sufferers have to take some 40 drugs, most of which to counter side effects of the anti-retrovirals they are taking.